CN110483383B - Preparation method of pyridine derivative - Google Patents
Preparation method of pyridine derivative Download PDFInfo
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- CN110483383B CN110483383B CN201810454988.7A CN201810454988A CN110483383B CN 110483383 B CN110483383 B CN 110483383B CN 201810454988 A CN201810454988 A CN 201810454988A CN 110483383 B CN110483383 B CN 110483383B
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of pyridine derivatives, which takes piperidine-4-ketone hydrochloride as a raw material to obtain a series of pyridine derivatives through halogenation and elimination reactions. Piperidine-4-ketone hydrochloride and a specific amount of halogenated reagent are respectively subjected to halogenation reaction to prepare 3, 5-dihalogenated piperidine-4-ketone, 3, 5-trihalopiperidine-4-ketone or 3,3,5, 5-tetrahalopiperidine-4-ketone, and then are subjected to elimination reaction with different types of alkaline reagents to obtain pyridine derivatives of which the 4-position is hydroxyl, amino or dimethylamino respectively. The method has the advantages of simple and convenient operation, mild conditions, short process flow, low wastewater amount, environmental protection and low cost, and is beneficial to the green industrial production of the pyridine derivative.
Description
Technical Field
The invention relates to a preparation method of a pyridine derivative, in particular to a preparation method of pyridine derivatives such as 4-hydroxypyridine, 4-aminopyridine, 4-dimethylaminopyridine, 3-chloro-4-hydroxypyridine, 3-bromo-4-hydroxypyridine, 3-chloro-4-aminopyridine, 3-bromo-4-aminopyridine, 3, 5-dichloro-4-hydroxypyridine, 3, 5-dibromo-4-hydroxypyridine, 3, 5-dichloro-4-aminopyridine and 3, 5-dibromo-4-aminopyridine, and belongs to the technical field of pharmaceutical and chemical industry.
Background
Hydroxypyridine (I1), also known as gamma-pyridone (gamma-pyridone), is an important organic synthesis intermediate, has wide application in the aspects of medicines, pesticides and the like, is an important raw material for synthesizing pyridine sulfonamide diuretics (toramide), and is also an important intermediate for synthesizing a high-efficiency acylation catalyst DMAP.
The synthesis of 4-hydroxypyridine is reported in Arzncim-forsch, 1998, 38(1):144-150 and Anyang college of academic and academic, 2006, 92-93, by condensation reaction of diethyl oxalate with acetone in the presence of sodium ethoxide, hydrolysis to produce chelidonic acid, ammoniation to produce chelidonic acid, and heating to decarboxylate to produce 4-hydroxypyridine.
In the synthetic route 1, a large amount of sodium ethoxide is needed, a single substituted product is easy to generate during a condensation reaction, a large amount of byproducts are generated, the product quality is seriously influenced, and meanwhile, the process has the advantages of long flow, complex operation, high requirement on equipment and low yield (64.5%), and is not suitable for industrial production.
In the chemical research 2001, 12(4)37-38 pyridine is chlorinated in ethyl acetate solvent by thionyl chloride to prepare a 4-pyridylpyridine dichloride intermediate, the pH value is adjusted to about 5 by sodium hydroxide solution, the 4-hydroxypyridine is prepared by hydrolysis at 130 ℃, and the quality of the product is further improved by recrystallization of chloroform. The total yield is 50% (calculated by pyridine)
In the synthetic route, several organic solvents such as ethyl acetate, ethanol, chloroform, benzene and the like are used, the consumption of the solvents is high, the requirements on the temperature and the pH value of reactants are high, and in the reaction process, black sticky substances are accompanied, so that the separation and the purification of products are very troublesome, and the synthetic route is only suitable for laboratory preparation.
Patent CN1560036 takes 4-aminopyridine as a starting material, and carries out diazotization reaction with sodium nitrite at room temperature in the presence of hydrochloric acid or sulfuric acid, and then carries out hydrolysis reaction to prepare 4-hydroxypyridine with the content of 99 percent and the yield of 95 percent.
However, 4-aminopyridine as a raw material is high in price, and the safety of the diazotization production operation is poor, so that the method is not beneficial to large-scale production.
The master academic thesis (Wangweizhong) of Nanjing university of science and technology is to oxidize and nitrify pyridine to obtain 4-nitropyridine-N-oxide compound, then to obtain 4-hydroxypyridine-N-oxide compound from 4-nitropyridine-N-oxide compound, and finally to reduce 4-hydroxypyridine-N-oxide compound to obtain the target product 4-hydroxypyridine with a total yield of 45.5%.
The route has long steps, complex operation and large amount of three wastes, and is not beneficial to environmental protection and industrial amplification.
4-aminopyridine (12), also known as para-aminopyridine, is an important intermediate for organic synthesis, medicine and dye synthesis, can be used for medical research, can be clinically used as a potassium channel inhibitor, and is used for treating neurological diseases such as myasthenia gravis and the like; and can be used as a substrate for molecular template reaction or a ligand for coordination chemistry research.
The proceedings of Tianjin institute of technology in literature 1999, 15, 80-82 and patents CN1807415, CN 106554306 and CN 107011255 use isonicotinic acid as starting material, prepare isonicotinic acid ethyl ester by sulfuric acid catalytic esterification, then react with ammonia water to prepare isonicotinic acid amide, and obtain 4-aminopyridine by Hofmann degradation under the action of bromine water, wherein the total yield is 50%.
However, the raw material isonicotinic acid used in the route is high in price, and strongly corrosive liquid bromine is needed, so that the industrial production has strict requirements on equipment materials, and strict protection measures are needed for great harm to human bodies.
According to the application of the literature, 4-cyanopyridine is used as a raw material in the chemical 2004,21(5) and CN 1311185, isonicotinamide is obtained through catalytic hydrolysis of Ni-Fe catalyst, and 4-aminopyridine is obtained through Hofmann degradation, wherein the yield is 71%.
Literature chemicals 1998, 20 (4): 240-241 and patent CN 1311185 take pyridine as raw material, N-pyridine oxide is obtained by oxidation and oxidation of hydrogen, then p-nitro-N-pyridine oxide is obtained by nitration of mixed acid, and 4-aminopyridine is prepared by reduction of iron powder or catalytic hydrogenation reduction of Raney nickel, with the total yield of 65.5-68.1%.
The method has the advantages of large wastewater quantity of nitration reaction, large consumption of solvent during reduction, complex post-treatment process and more wastewater and waste residues.
Patent CN106243021 uses 4-chloropyridine as raw material, and reacts with liquid ammonia under the action of catalyst (ferric chloride, zinc chloride, copper chloride) at 30-90 deg.C and 0.8-3.0MPa for 4-15 hours to prepare 4-aminopyridine.
4-dimethylamino pyridine (I3) is a novel efficient acylation catalyst, and has been widely applied to the acylation and ester exchange of alcohol, enol, amine, phenol, enol ester and isonitrile acid ester, alcohol etherification and other organic reactions. In addition, DMAP can also be used as a reverse phase transfer catalyst for interfacial reactions. Because the DMAP has the advantages of high reaction speed, mild conditions, wide applicable solvents, high product yield and the like, is suitable for acylation reaction of alcohols with large steric hindrance and some hydroxyl and amino compounds which are unstable to acid, and is widely applied to the production fields of fine chemicals such as medicines, pesticides, spices, petrochemical industry and the like.
The document Henan chemical 1997, 10, 15-16 uses pyridine as raw material, and prepares 4-dimethylamino pyridine by five steps of oxidation, nitration, chlorination, amination and reduction, and the total yield reaches 58.9%. The method has long reaction route, long production period and large amount of waste water.
Chinese pharmaceutical industry, 1993, 24 (7): 321 takes pyridine and thionyl chloride as raw materials to prepare an intermediate 4- (4-pyridyl) pyridinium chloride hydrochloride, and then the intermediate reacts with dimethylamine or dimethylformamide to generate 4-dimethylaminopyridine. The method has high temperature requirement and low total yield.
Patent CN103787963A uses 4-cyanopyridine as raw material, quaternizes with acrylic acid, and then reacts with amination reagent to prepare 4-dimethylamino pyridine. But the price of the used raw materials is high, which is not beneficial to cost control and is not suitable for large-scale industrial production.
In addition, 3-chloro-4-hydroxypyridine (I4), 3-bromo-4-hydroxypyridine (I5), 3-chloro-4-aminopyridine (I6), 3-bromo-4-aminopyridine (I7), 3, 5-dichloro-4-hydroxypyridine (I8), 3, 5-dibromo-4-hydroxypyridine (I9), 3, 5-dichloro-4-aminopyridine (I10), and 3, 5-dibromo-4-aminopyridine (I11) are important pyridine derivatives, of which 3, 5-dichloro-4-aminopyridine (I10) is a key intermediate for the preparation of roflumilast.
In the patent US5935978, 4-aminopyridine is used as a raw material, and hydrochloric acid and hydrogen peroxide are utilized to prepare 3, 5-dichloro-4-aminopyridine through chlorination reaction. The price of the raw material 4-aminopyridine is high, the density of the electron cloud of the 4-aminopyridine is high, the 4-aminopyridine is easy to be oxidized and generate sticky byproducts, and the method is not suitable for industrial production.
In conclusion, the preparation method of the pyridine derivative in the prior art has the problems of complex process, high raw material cost, low yield, no contribution to environmental protection, industrial production and the like. Therefore, the establishment of a general preparation method of green and low-cost 4-hydroxypyridine, 4-aminopyridine, 4-dimethylaminopyridine, 3-chloro-4-hydroxypyridine, 3-bromo-4-hydroxypyridine, 3-chloro-4-aminopyridine, 3-bromo-4-aminopyridine, 3, 5-dichloro-4-hydroxypyridine, 3, 5-dibromo-4-hydroxypyridine, 3, 5-dichloro-4-aminopyridine and 3, 5-dibromo-4-aminopyridine has important significance for the development and industrial production of downstream medicines and chemical products.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of the pyridine derivative, and the method has the advantages of simple and convenient operation, mild conditions, short process flow, low wastewater amount, environmental protection, low cost and high yield.
The technical scheme of the invention is as follows:
a method for preparing pyridine derivatives, comprising the steps of:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenated reagent to obtain 3, 5-dihalogenated piperidine-4-ketone, 3, 5-trihalopiperidine-4-ketone or 3,3,5, 5-tetrahalopiperidine-4-ketone, filtering after the reaction is finished, distilling to recover the solvent, and directly using the remainder without distillation for next elimination reaction;
(2) elimination reaction: in a proper solvent B, 3, 5-dihalogenated piperidine-4-ketone, 3, 5-trihalopiperidine-4-ketone or 3,3,5, 5-tetrahalopiperidine-4-ketone obtained in the step (1) reacts with an alkaline reagent, and the corresponding pyridine derivatives I1 to I11 are obtained through elimination reaction.
The structural formulas of I1 to I11 are shown as follows:
according to the method of the present invention, the preferred process conditions and amounts in the steps are as follows:
preferably, the solvent A in the step (1) is one or a combination of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloromethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene or no solvent, and the mass ratio of the solvent A to the piperidine-4-one hydrochloride is (5-15): 1.
Preferably, the acid-binding agent in the step (1) is one or a combination of potassium carbonate, calcium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide, and the molar ratio of the acid-binding agent to the piperidine-4-one hydrochloride is (0.0-2.0): 1.
Preferably, the halogenating reagent in the step (1) is one or a combination of chlorine, N-chlorosuccinimide, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, bromine, N-bromosuccinimide, hydrobromic acid-sodium bromate and hydrobromic acid-hydrogen peroxide, the dosage of the halogenating reagent is determined according to a target halogenating product, the molar ratio of the halogenating reagent to the piperidine-4-one hydrochloride is (2.0-5.0): 1, and the further preferable molar ratio is (2.1-4.5): 1.
Preferably, the temperature of the halogenation reaction in the step (1) is 10-80 ℃, and the reaction is carried out for 2-8 hours. Preferably, the temperature of the halogenation reaction is 40-60 ℃ and the reaction time is 4-6 hours.
Preferably, the solvent B in the step (2) is one or a combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran or no solvent, and the weight ratio of the solvent B to the 3, 5-dihalopiperidine-4-one, the 3,3, 5-trihalopiperidine-4-one or the 3,3,5, 5-tetrahalopiperidine-4-one is (5-15): 1.
Preferably, the alkaline reagent in the step (2) is inorganic base, ammonia water or ammonia alcohol solution with certain concentration, dimethylamine water solution with certain concentration or dimethylamine alcohol solution; the inorganic base is potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide; the molar ratio of the alkaline reagent to the 3, 5-dihalopiperidin-4-one, the 3,3, 5-trihalopiperidin-4-one or the 3,3,5, 5-tetrahalopiperidin-4-one is (2.0 to 5.0):1, and more preferably (2.5 to 4.0): 1. Further preferably, the mass concentration of the ammonia water or the ammonia alcohol solution is 10-30%; the mass concentration of the dimethylamine aqueous solution or dimethylamine alcohol solution is 7-30%.
Preferably, the reaction temperature in the step (2) is 10-80 ℃, and the reaction lasts 2-8 hours. Further preferably, the temperature of the elimination reaction is 30 to 50 ℃ and the reaction is carried out for 3 to 5 hours.
The process of the present invention is depicted as the following synthetic scheme 12:
wherein X is Br, Cl or H; b is OH or NH2、NMe2。
The invention has the technical characteristics and beneficial effects that:
1. the invention takes piperidine-4-ketone hydrochloride as a raw material, and a series of pyridine derivatives are obtained through halogenation reaction and elimination reaction. The raw materials are cheap and easy to obtain, the route is short, the amount of three wastes is small, and the method is favorable for safe and environment-friendly industrial production.
2. The invention uses piperidine-4-ketone hydrochloride and a specific amount of halogenating reagent to carry out halogenation reaction to obtain 3, 5-dihalogenated piperidine-4-ketone, 3, 5-trihalopiperidine-4-ketone or 3,3,5, 5-tetrahalopiperidine-4-ketone, controls the halogenating number according to the dosage of the halogenating reagent to obtain a corresponding halogenated product, and has high reaction selectivity and high yield which can reach more than 88.6 percent.
3. The invention utilizes different types of alkaline reagents and optimizes the dosage to respectively react with 3, 5-dihalogenated piperidine-4-ketone, 3, 5-trihalopiperidine-4-ketone or 3,3,5, 5-tetrahalopiperidine-4-ketone to obtain the pyridine derivative of which the 4-position is hydroxyl, amino or dimethylamino respectively through elimination reaction, and the invention has high reaction selectivity, is easy to carry out and is convenient for the series preparation of products.
4. The method has the advantages of simple and convenient operation, mild conditions, short process flow, low wastewater amount, environmental protection and low cost, and is beneficial to the green industrial production of the pyridine derivative.
Detailed Description
The following examples and comparative examples are provided to fully illustrate the technical solution of the present invention in detail, but the present invention is not limited to the following examples. Any non-inventive arrangements or embodiments derived from the embodiments of the present invention or any variations of the non-inventive implementation sequences based on the embodiments of the present invention by those skilled in the art are within the scope of the present invention.
The piperidine-4-one hydrochloride used as the starting material in the examples was provided by the pharmaceutical company Jinan Ruihui or prepared according to the prior art, and the other starting materials and reagents were all commercially available products. In the examples, "%" is given by weight unless otherwise specified.
Example 1: preparation of 3, 5-dichloropiperidine-4-one
200 g of chloroform, 27.1 g (0.2 mol) of piperidine-4-ketone hydrochloride are put into a 500 ml four-neck flask connected with a stirring thermometer and a reflux condenser tube, chlorine gas is introduced between 40 ℃ and 45 ℃, 32.0 g of chlorine gas is introduced, the mixture is stirred and reacted for 5 hours at 40 ℃ to 45 ℃, the mixture is cooled to 20 ℃ to 25 ℃, the nitrogen gas blows residual chlorine gas and byproduct hydrogen chloride gas, the mixture is blown for 2 hours, 50 g of water is added, the pH value is adjusted to 7 to 8 by 20 percent of sodium carbonate aqueous solution, the organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, the layer is separated, the solvent is recovered by distillation, 39.9 g of light yellow liquid 3, 5-dichloropiperidin-4-ketone is obtained, and the light yellow liquid is directly used for relevant elimination reaction.
Example 2: preparation of 3, 5-dibromopiperidin-4-one
In a 500 ml four-neck flask connected with a stirring, thermometer and reflux condenser, 200 g of chloroform, 13.6 g (0.1 mol) of piperidine-4-one hydrochloride and 41.0 g (0.2 mol) of 40% hydrobromic acid are added dropwise at 30-35 ℃ with 24.0(0.21 mol) of 30% hydrogen peroxide, the mixture is dripped for about 2 hours, the mixture is stirred and reacted at 30-35 ℃ for 3 hours, 50 g of water is added, the pH value is adjusted to 7-8 by 20% sodium carbonate aqueous solution, the mixture is layered, an organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, the layer is separated, the solvent is distilled and recovered, 29.2 g of yellow liquid 3, 5-dibromopiperidin-4-one is obtained and is directly used for related elimination reaction.
Example 3: preparation of 3,3, 5-trichloropiperidin-4-one
In a 500 ml four-neck flask connected with a stirring, thermometer and reflux condenser, 200 g of dichloromethane, 27.1 g (0.2 mol) of piperidine-4-one hydrochloride and 43.0 g (0.41 mol) of 35% hydrochloric acid are added with 74.0(0.65 mol) of 30% hydrogen peroxide dropwise at 30-35 ℃ until dropping is completed for about 3 hours, then the mixture is stirred and reacted for 3 hours at 40-45 ℃, cooled to 20-25 ℃, nitrogen is blown to remove residual chlorine and hydrogen chloride gas for 1 hour, 50 g of water is added, the pH value is adjusted to 7-8 by 20% sodium carbonate aqueous solution, layers are separated, the organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, layers are separated, the solvent is recovered by distillation, 47.4 g of yellow liquid 3,3, 5-trichloropiperidine-4-one is obtained and is directly used for related elimination reaction.
Example 4: preparation of 3,3, 5-tribromopiperidin-4-one
In a 500 ml four-neck flask connected with a stirring, thermometer and reflux condenser, 200 g of dichloromethane, 13.6 g (0.1 mol) of piperidine-4-one hydrochloride and 61.0 g (0.3 mol) of 40% hydrobromic acid are added dropwise at 30-35 ℃ with 36.5(0.32 mol) of 30% hydrogen peroxide, the mixture is dripped for about 2 hours, the mixture is stirred and reacted at 30-35 ℃ for 3 hours, 50 g of water is added, the pH value is adjusted to 7-8 by 20% sodium carbonate aqueous solution, the mixture is layered, an organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, the solvent is distilled and recovered, and 37.1 g of yellow liquid 3,3, 5-tribromopiperidine-4-ketone is obtained and is directly used for related elimination reaction.
Example 5: preparation of 3,3,5, 5-tetrachloropiperidin-4-one
200 g of dichloromethane, 27.1 g (0.2 mol) of piperidine-4-one hydrochloride and 75 g of 35% hydrochloric acid are added dropwise to 100.0(0.88 mol) of 30% hydrogen peroxide at 30-35 ℃ in a 500 ml four-neck flask connected with a stirring, thermometer and reflux condenser, after dropping for about 3 hours, the mixture is stirred and reacted at 40-45 ℃ for 3 hours, cooled to 20-25 ℃, nitrogen is used for blowing residual chlorine and hydrogen chloride gas, the residual chlorine and hydrogen chloride gas are blown for 1 hour, 50 g of water is added, the pH value is adjusted to 7-8 by 20% sodium carbonate aqueous solution, layers are separated, the organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, layers are separated, the solvent is distilled and recovered, and 55.0 g of yellow liquid 3,3,5, 5-tetrachloropiperidine-4-one is obtained and is directly used for related elimination reaction.
Example 6: preparation of 3,3,5, 5-tetrabromopiperidin-4-one
In a 500 ml four-neck flask connected with a stirring, thermometer and reflux condenser, 200 g of dichloromethane, 13.6 g (0.1 mol) of piperidine-4-one hydrochloride and 85.0 g (0.4 mol) of 40% hydrobromic acid are added dropwise at 30-35 ℃ with 50.0(0.44 mol) of 30% hydrogen peroxide, 2 hours are completely dropped, the mixture is stirred and reacted at 30-35 ℃ for 3 hours, 50 g of water is added, the pH value is adjusted to 7-8 by 20% sodium carbonate aqueous solution, the mixture is layered, an organic phase is washed for 1 time by 20 g of saturated sodium chloride aqueous solution, the solvent is distilled and recovered, 45.0 g of yellow liquid 3,3,5, 5-tetrabromopiperidin-4-one is obtained and is directly used for related elimination reaction.
Example 7: preparation of 4-hydroxypyridine
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of tetrahydrofuran, 10.2 g (0.05 mol) of 3, 5-dichloropiperidine-4-one obtained in example 1, 10.0 g of potassium carbonate, and stirring at 40 to 45 ℃ for reaction for 3 hours, cooling to 20 to 25 ℃, filtering, washing the filter cake with 20 g of a solvent, combining the filtrates, and recovering the solvent by distillation to obtain 4.43 g of 4-hydroxypyridine as a white solid in a yield of 93.3% (based on piperidine-4-one hydrochloride) and a liquid phase purity of 99.1%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.26(d,2H),6.86(d,2H),5.36(s,1H)。
example 8: preparation of 4-aminopyridines
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of methylene chloride, 14.7 g (0.05 mol) of 3, 5-dibromopiperidin-4-one obtained in example 2, 20.0 g (0.2 mol) of 17% aqueous ammonia, and stirring at 40 to 45 ℃ for 4 hours, cooling to 20 to 25 ℃, separating the layers, extracting the aqueous layer with methylene chloride for 2 times (20 g each time), combining the organic phases, and recovering the solvent by distillation to obtain 4.26 g of 4-aminopyridine, the yield being 90.6% (based on the hydrochloride of piperidin-4-one) and the purity of the liquid phase being 98.6%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.37(d,2H),7.01(d,2H),4.23(br,2H)。
example 9: preparation of 4-dimethylaminopyridine
To a 500 ml autoclave, 100 g of methanol, 14.7 g (0.05 mol) of 3, 5-dibromopiperidin-4-one obtained in example 2, 30 g (0.2 mol) of a 30% dimethylamine-methanol solution were added, and the mixture was stirred at 40 to 45 ℃ for 4 hours, cooled to 20 to 25 ℃, filtered, and the cake (dimethylamine hydrobromide) was washed with 20 g of a solvent, and the filtrates were combined and distilled to recover the solvent, whereby 5.47 g of 4-dimethylaminopyridine was obtained in a yield of 89.7% (based on the piperidine-4-one hydrochloride) and a liquid phase purity of 98.9%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.14(d,2H),6.98(d,2H),2.62(s,6H)。
example 10: preparation of 3-chloro-4-hydroxypyridine
In a 500 ml four-neck flask equipped with a stirring, thermometer and reflux condenser, 130 g of methanol, 12.0 g (0.05 mol) of 3,3, 5-trichloropiperidin-4-one obtained in example 3, 4.1 g of sodium hydroxide were reacted at 40 to 45 ℃ for 2 hours with stirring, cooled to 20 to 25 ℃, filtered, the filter cake was washed with 20 g of solvent, the filtrate was combined, and the solvent was recovered by distillation to obtain 5.74 g of 3-chloro-4-hydroxypyridine as a white solid in 88.6% yield (based on piperidin-4-one hydrochloride) and 99.3% purity of the liquid phase.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):9.93(s,1H),8.63(d,1H),8.11(d,1H),6.18(s,1H)。
example 11: preparation of 3-bromo-4-hydroxypyridine
In a 500 ml four-neck flask equipped with a stirrer, a thermometer and a reflux condenser, 130 g of chloroform, 18.6 g (0.05 mol) of 3,3, 5-tribromopiperidin-4-one obtained in example 4 and 17.5 g of potassium carbonate were reacted at 35 to 40 ℃ with stirring for 2 hours, cooled to 20 to 25 ℃, filtered, the filter cake was washed with 20 g of solvent, the filtrate was combined, and the solvent was recovered by distillation to obtain 7.77 g of 3-bromo-4-hydroxypyridine as a white solid in 89.3% yield (based on piperidin-4-one hydrochloride) and 99.1% purity of the liquid phase.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.33(s,1H),8.20(d,1H),6.93(d,1H),5.36(s,1H)。
example 12: preparation of 3-chloro-4-aminopyridine
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of methylene chloride, 12.0 g (0.05 mol) of 3,3, 5-trichloropiperidin-4-one obtained in example 3, 30.0 g (0.3 mol) of 17% ammonia water were reacted at 35 to 40 ℃ with stirring for 4 hours, cooled to 20 to 25 ℃, separated, the aqueous layer was extracted with methylene chloride for 2 times (20 g each time), the organic phases were combined, and the solvent was recovered by distillation to obtain 5.75 g of 3-chloro-4-aminopyridine, the yield was 89.5% (the yield was in terms of piperidin-4-one hydrochloride) and the purity of the liquid phase was 98.9%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.65(s,1H),8.61(d,1H),7.13(d,1H),4.14(br,2H)。
example 13: preparation of 3-bromo-4-aminopyridine
In a 500 ml four-neck flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of dichloromethane, 18.6 g (0.05 mol) of 3,3, 5-tribromopiperidin-4-one obtained in example 4, 30.0 g (0.3 mol) of 17% ammonia water, stirring and reacting at 35-40 ℃ for 4 hours, cooling to 20-25 ℃, layering, extracting the water layer with dichloromethane for 2 times (20 g each time), combining the organic phases, and recovering the solvent by distillation to obtain 7.8 g of 3-bromo-4-aminopyridine, wherein the yield is 90.2% (the yield is calculated as piperidine-4-one hydrochloride) and the purity of the liquid phase is 99.1%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.14(s,1H),7.96(d,1H),6.68(d,1H),4.43(br,2H)。
example 14: preparation of 3, 5-dichloro-4-hydroxypyridine
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 130 g of methanol, 13.7 g (0.05 mol) of 3,3,5, 5-tetrachloropiperidin-4-one obtained in example 5, 16.6 g of potassium carbonate were reacted at 50 to 55 ℃ with stirring for 3 hours, cooled to 20 to 25 ℃, filtered, the filter cake was washed with 20 g of a solvent, the filtrate was combined, and the solvent was recovered by distillation to obtain 7.47 g of 3, 5-dichloro-4-hydroxypyridine as a white solid in a yield of 91.1% (based on the piperidine-4-one hydrochloride) and a liquid phase purity of 99.1%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.62(s,2H),5.76(s,1H)。
example 15: preparation of 3, 5-dibromo-4-hydroxypyridine
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 130 g of tetrahydrofuran, 22.6 g (0.05 mol) of 3,3,5, 5-tetrabromopiperidin-4-one obtained in example 6, 16.6 g of potassium carbonate, and stirring at 50 to 55 ℃ for reaction for 3 hours, cooling to 20 to 25 ℃, filtering, washing the filter cake with 20 g of a solvent, combining the filtrates, and distilling to recover the solvent, 11.5 g of white solid 3, 5-dibromo-4-hydroxypyridine was obtained in a yield of 90.9% (based on piperidine-4-one hydrochloride) and a liquid phase purity of 99.2%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.56(s,2H),5.36(s,1H)。
example 16: preparation of 3, 5-dichloro-4-aminopyridine
Into a 500 ml autoclave, 130 g of methanol, 13.7 g (0.05 mol) of 3,3,5, 5-tetrachloropiperidin-4-one obtained in example 5 and 35.0 g (0.2 mol) of 10% methanolic ammonia were charged, stirred at 40-45 ℃ for 4 hours, cooled to 20-25 ℃, filtered, the filter cake was washed with 20 g of solvent, the filtrates were combined and the solvent was recovered by distillation to obtain 7.31 g of 3, 5-dichloro-4-aminopyridine as a white solid with a yield of 89.7% (based on piperidin-4-one hydrochloride) and a liquid phase purity of 99.3%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.71(s,2H),4.35(br,2H)。
example 17: preparation of 3, 5-dibromo-4-aminopyridine
Into a 500 ml autoclave, 130 g of methanol, 22.6 g (0.05 mol) of 3,3,5, 5-tetrabromopiperidin-4-one obtained in example 6 and 34.0 g (0.2 mol) of a 10% ammonia methanol solution were charged, stirred at 45 to 50 ℃ for reaction for 3 hours, cooled to 20 to 25 ℃, filtered, the filter cake was washed with 20 g of a solvent, the filtrates were combined, and the solvent was recovered by distillation to obtain 11.5 g of 3, 5-dibromo-4-aminopyridine as a white solid with a yield of 91.3% (based on piperidine-4-one hydrochloride) and a liquid phase purity of 99.0%.
The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,δ,ppm):8.12(s,2H),4.39(br,2H)。
comparative example 1: preparation of 3, 5-dibromopiperidin-4-one
Into a 500 ml four-neck flask equipped with a stirrer, a thermometer and a reflux condenser, 200 g of chloroform, 13.6 g (0.1 mol) of piperidin-4-one hydrochloride and 44.5 g (0.22 mol) of 40% hydrobromic acid were added dropwise at 30 to 35 ℃ with 25.0(0.22 mol) of 30% hydrogen peroxide, and after dropping for about 2 hours, the mixture was stirred at 30 to 35 ℃ for reaction for 3 hours, adding 50 g of water, adjusting the pH value to 7-8 by using a 20% sodium carbonate aqueous solution, layering, washing an organic phase for 1 time by using 20 g of a saturated sodium chloride aqueous solution, layering, distilling and recovering a solvent to obtain 32.3 g of yellow liquid, wherein the gas phase area ratio of 3, 5-dibromopiperidin-4-one to 3,3, 5-tribromopiperidin-4-one is 81.3%: 18.2% containing 18.2% tribromo by-products, difficult to purify by distillation and recrystallization, not favoured for the products used for the related elimination reactions.
Comparative example 2: preparation of 4-hydroxypyridine
In a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of tetrahydrofuran were introduced to obtain 32.3 g of a mixture of 3, 5-dibromopiperidin-4-one and 3,3, 5-tribromopiperidin-4-one obtained in comparative example 1, 20.0 g of potassium carbonate was reacted at 40 to 45 ℃ with stirring for 3 hours, the reaction mixture was cooled to 20 to 25 ℃, filtered, the filter cake was washed with 20 g of a solvent, the filtrates were combined, the solvent was recovered by distillation to obtain 10.9 g of a white solid containing 7.6 g of 4-hydroxypyridine and 3.3 g of 3-bromo-4-hydroxypyridine, and the mixture was recrystallized twice from n-hexane and ethyl acetate (volume ratio: 3:1) to obtain 5.2 g of 4-hydroxypyridine in a total yield of 54.7% in two steps based on the hydrochloride of piperidin-4-one used in comparative example 1, the purity of the liquid phase is 98.3%.
Comparative example 3: preparation of 4-dimethylaminopyridine
To a 500 ml autoclave, 100 g of methanol, 14.7 g (0.05 mol) of 3, 5-dibromopiperidin-4-one obtained in example 2, 15 g (0.1 mol) of a 30% dimethylamine-methanol solution, stirred at 40 to 45 ℃ for 4 hours, cooled to 20 to 25 ℃, filtered, the cake (dimethylamine hydrobromide) was washed with 20 g of a solvent, the filtrates were combined and the solvent was recovered by distillation to obtain 5.12 g of a solid, which contained 3.41 g of 4-dimethylaminopyridine and 1.26 g of 4-hydroxypyridine by a liquid phase external standard method and was further purified.
The purification method comprises the following steps: the resulting 5.12 g of crude solid was dissolved in 100 g of dichloromethane, 10 g of 15% aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature for 1 hour, the layers were separated, the organic phase was washed with 10 g of saturated aqueous sodium chloride solution, the organic phase was dried over 2.0 g of anhydrous sodium sulfate for 4 hours, and the filtrate was concentrated to give 3.28 g of 4-dimethylaminopyridine in 53.8% yield and 98.5% purity of the liquid phase.
From the above comparative examples 1 to 3, it can be seen that:
the amount of the halogenating agent and the alkaline agent is the key step of the invention, comparative example 1 shows that the control of the amount of the halogenating agent is very important for controlling the halogenation degree, if the amount of the halogenating agent is insufficient, a mixture of 3-bromopiperidin-4-one and 3, 5-dibromopiperidin-4-one is obtained; the amount of the halogenated reagent is large, and the mixture of the 3,3, 5-tribromopiperidin-4-one and the 3, 5-dibromopiperidin-4-one is difficult to purify and is not beneficial to directly carrying out the elimination reaction in the step (2). The content of elimination reaction products is low, multiple purification is needed, and the yield is low. Reference is made specifically to comparative example 2. Comparative example 3 shows that the amount of the alkali agent used in the elimination reaction of step (2) is sufficient, and 1 equivalent of the alkali agent is required for each elimination of hydrogen halide, and if the amount of the alkali agent is insufficient, the amount of the by-product is large, and a special purification treatment is required, and the yield is low.
Claims (12)
1. A preparation method of a pyridine derivative I1 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenating reagent to obtain 3, 5-dihalogenopiperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: reacting the 3, 5-dihalogenated piperidine-4-ketone obtained in the step (1) with an alkaline reagent in a proper solvent B to obtain a corresponding pyridine derivative I1 through elimination reaction; the alkaline reagent is inorganic alkali; the inorganic base is potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide; the molar ratio of the alkaline reagent to the 3, 5-dihalogenated piperidine-4-ketone is (2.0-5.0): 1; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formula of formula I1 is shown below:
2. a preparation method of a pyridine derivative I2 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenating reagent to obtain 3, 5-dihalogenopiperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: reacting the 3, 5-dihalogenated piperidine-4-ketone obtained in the step (1) with an alkaline reagent in a proper solvent B to obtain a corresponding pyridine derivative I2 through elimination reaction; the alkaline reagent is ammonia water or ammonia alcohol solution with certain concentration; the molar ratio of the alkaline reagent to the 3, 5-dihalogenated piperidine-4-ketone is (2.0-5.0): 1; the mass concentration of the ammonia water and the ammonia solution is 10-30%; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formula of formula I2 is shown below:
3. a preparation method of a pyridine derivative I3 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenating reagent to obtain 3, 5-dihalogenopiperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: reacting the 3, 5-dihalogenated piperidine-4-ketone obtained in the step (1) with an alkaline reagent in a proper solvent B to obtain a corresponding pyridine derivative I3 through elimination reaction; the alkaline reagent is dimethylamine aqueous solution or dimethylamine alcoholic solution with certain concentration; the molar ratio of the alkaline reagent to the 3, 5-dihalogenated piperidine-4-ketone is (2.0-5.0): 1; the mass concentration of the dimethylamine aqueous solution or dimethylamine alcohol solution is 7-30%; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formula of formula I3 is shown below:
4. a preparation method of pyridine derivatives I4-I5 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of a halogenating reagent to obtain 3,5, 5-trihalogen piperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: in a proper solvent B, 3,5, 5-trihalopiperidine-4-ketone obtained in the step (1) reacts with an alkaline reagent to obtain corresponding pyridine derivatives I4-I5 through elimination reaction; the alkaline reagent is inorganic alkali; the inorganic base is potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide; the molar ratio of the alkaline reagent to the 3,5, 5-trihalopiperidine-4-one is (2.0-5.0): 1; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formulae of formulae I4 to I5 are shown below:
5. a preparation method of pyridine derivatives I6-I7 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of a halogenating reagent to obtain 3,5, 5-trihalogen piperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: in a proper solvent B, 3,5, 5-trihalopiperidine-4-ketone obtained in the step (1) reacts with an alkaline reagent to obtain corresponding pyridine derivatives I6-I7 through elimination reaction; the alkaline reagent is ammonia water or ammonia alcohol solution with certain concentration; the molar ratio of the alkaline reagent to the 3,5, 5-trihalopiperidine-4-one is (2.0-5.0): 1; the mass concentration of the ammonia water and the ammonia solution is 10-30%; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formulae of formulae I6 to I7 are shown below:
6. a preparation method of pyridine derivatives I8-I9 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenating reagent to obtain 3,3,5, 5-tetrahalogenated piperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: in a proper solvent B, 3,5, 5-tetrahalogenated piperidine-4-ketone obtained in the step (1) reacts with an alkaline reagent, and the elimination reaction is carried out to obtain corresponding pyridine derivatives I8-I9; the alkaline reagent is inorganic alkali; the inorganic base is potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide; the molar ratio of the alkaline reagent to the 3,3,5, 5-tetrahalogenated piperidine-4-ketone is (2.0-5.0) to 1; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formulae of formulae I8 to I9 are shown below:
7. a preparation method of pyridine derivatives I10-I11 is characterized by comprising the following steps:
(1) and (3) halogenation reaction: in the presence of a proper solvent A, an acid-binding agent or no acid-binding agent, carrying out halogenation reaction on piperidine-4-ketone hydrochloride and a certain amount of halogenating reagent to obtain 3,3,5, 5-tetrahalogenated piperidine-4-ketone; the halogenated reagent is selected from hydrochloric acid-hydrogen peroxide, hydrobromic acid-hydrogen peroxide or a combination thereof, and the dosage of the halogenated reagent is determined according to a target halogenated product; after the reaction is finished, filtering, distilling to recover the solvent, and directly using the remainder for the next elimination reaction without distillation; the solvent A is one or the combination of dichloromethane, trichloromethane, carbon tetrachloride, normal hexane, cyclohexane, petroleum ether, tetrahydrofuran, benzene and toluene;
(2) elimination reaction: in a proper solvent B, 3,5, 5-tetrahalogenated piperidine-4-ketone obtained in the step (1) reacts with an alkaline reagent, and the elimination reaction is carried out to obtain corresponding pyridine derivatives I10-I11; the alkaline reagent is ammonia water or ammonia alcohol solution with certain concentration; the molar ratio of the alkaline reagent to the 3,3,5, 5-tetrahalogenated piperidine-4-ketone is (2.0-5.0) to 1; the mass concentration of the ammonia water and the ammonia solution is 10-30%; the solvent B is one of or the combination of dichloromethane, trichloromethane, methanol, ethanol, tetrahydrofuran and 2-methyltetrahydrofuran;
the structural formulas of I10 to I11 are shown as follows:
8. the production method according to any one of claims 1 to 7, wherein the mass ratio of the solvent A and the piperidin-4-one hydrochloride in the step (1) is (5-15): 1.
9. The preparation method of any one of claims 1 to 7, wherein the acid-binding agent in step (1) is one or a combination of potassium carbonate, calcium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide, and the molar ratio of the acid-binding agent to the piperidine-4-one hydrochloride is (0.0-2.0): 1.
10. The process according to any one of claims 1 to 7, wherein the halogenation reaction in the step (1) is carried out at a temperature of 10 to 80 ℃ for 2 to 8 hours.
11. The process according to any one of claims 1 to 7, wherein the weight ratio of the solvent B to the 3, 5-dihalopiperidin-4-one, 3, 5-trihalopiperidin-4-one or 3,3,5, 5-tetrahalopiperidin-4-one in step (2) is (5-15): 1.
12. The process according to any one of claims 1 to 7, wherein the elimination reaction in step (2) is carried out at a temperature of 10 to 80 ℃ for 2 to 8 hours.
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| US4267378A (en) * | 1976-08-12 | 1981-05-12 | Carl E. Van Winckel | 2,2-Dialkoxy-6-chlorocyclohexanones |
| WO1999050244A1 (en) * | 1998-03-28 | 1999-10-07 | Lipitek, Inc. | Nitroxide free radical dual indicator agents |
| CN105348285A (en) * | 2015-12-02 | 2016-02-24 | 新发药业有限公司 | Low-cost and high-yield adenine preparation method |
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| US4267378A (en) * | 1976-08-12 | 1981-05-12 | Carl E. Van Winckel | 2,2-Dialkoxy-6-chlorocyclohexanones |
| WO1999050244A1 (en) * | 1998-03-28 | 1999-10-07 | Lipitek, Inc. | Nitroxide free radical dual indicator agents |
| CN105348285A (en) * | 2015-12-02 | 2016-02-24 | 新发药业有限公司 | Low-cost and high-yield adenine preparation method |
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| A of Bromine Monochloride on Cyclohexanol, Cyclohexanone & Cyclopentanone;Lalitha Gnanadoss et al.;《Indian Journal of Chemistry》;19791231;第18B卷(第4期);第375-376页 * |
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