CN110483383A - A kind of preparation method of pyridine derivate - Google Patents
A kind of preparation method of pyridine derivate Download PDFInfo
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- CN110483383A CN110483383A CN201810454988.7A CN201810454988A CN110483383A CN 110483383 A CN110483383 A CN 110483383A CN 201810454988 A CN201810454988 A CN 201810454988A CN 110483383 A CN110483383 A CN 110483383A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Abstract
The present invention relates to a kind of preparation method of pyridine derivate, this method obtains a series of pyridine derivates using piperidin-4-one hydrochloride as raw material, through halogenating reaction and elimination reaction.3 are prepared respectively through halogenating reaction with the halogenating agent of piperidin-4-one hydrochloride and specific quantity, 5- dihalo piperidin-4-one, 3,3, tri- halopiperidine -4- ketone of 5- or 3,3,5,5- tetra- halopiperidine -4- ketone, then with different types of alkaline reagent, through elimination reaction obtain 4- be respectively hydroxyl, amino or dimethylamino pyridine derivate elimination reaction.Operation of the present invention is easy, and mild condition, process flow is short, and wastewater flow rate is low, environmentally protective, at low cost, is conducive to the green industrialized production of the pyridine derivate.
Description
Technical field
The present invention relates to a kind of preparation methods of pyridine derivate, and in particular to pyridine derivate 4- pyridone, 4- ammonia
Yl pyridines, 4-dimethylaminopyridine, 3- chloro-4-hydroxyl pyridine, the bromo- 4- pyridone of 3-, the chloro- 4-aminopyridine of 3-, the bromo- 4- of 3-
Aminopyridine, the chloro- 4- pyridone of 3,5- bis-, the bromo- 4- pyridone of 3,5- bis-, the chloro- 4-aminopyridine of 3,5- bis- and 3,5- bis-
The preparation method of bromo- 4-aminopyridine, belongs to pharmaceutical chemistry technical field.
Background technique
Pyridone (I1) also known as γ-pyridine ketone (γ-pyridone), the entitled 4-hydroxypyridine of English,
A kind of important organic synthesis intermediate, medicine, in terms of have been widely used, it is pyridine synthesis sulfonamides
The important source material of diuretics (torasamide) and the important intermediate of synthesizing efficient acylation catalyst DMAP.
The synthetic method of 4- pyridone is rarely reported, document Arzncim-forsch, 1998,38 (1): 144-150 and
Anyang Teachers College's journal 2006, with acetone condensation reaction occurs for 92-93 in the presence of sodium ethoxide with diethy-aceto oxalate, then hydrolyzes
Chelidonic acid is made, then carries out ammonification and generates chelidamic acid, 4- pyridone is made finally by heating decarboxylation.
Synthetic route 1 needs to be easy to happen mono-substituted products, by-product in condensation reaction using a large amount of sodium ethoxide
It is more, the quality of product is seriously affected, while this process flow is long, complicated for operation, the high requirements on the equipment, yield is relatively low
(64.5%), be not suitable for industrialized production.
Pyridine is made two with thionyl chloride chlorination in ethyl acetate solvent by 2001,12 (4) 37-38 of document chemical research
Chlorination 4- pyridyl group pyridine intermediate, then pH value is adjusted to 5 or so through sodium hydroxide solution, it hydrolyzes, is made at a temperature of 130 DEG C
4- pyridone further increases the quality of product by Gossypol recrystallized from chloroform.Total recovery is 50% (in terms of pyridine)
In this synthetic route, to use to several organic solvents such as ethyl acetate, ethyl alcohol, chloroform, benzene, solvent consumption is very
Greatly, while to the temperature of reactant, pH value control require it is relatively high, and during the reaction, with the dope of black,
Separation and purification to product bring it is cumbersome, be appropriate only for laboratory preparation.
Patent CN1560036 is using 4-aminopyridine as starting material, with sodium nitrite in room in the presence of hydrochloric acid or sulfuric acid
Temperature is lower to occur diazo-reaction, then through hydrolysis, 4- pyridone, content 99%, yield 95% is made.
But raw material 4-aminopyridine price is high, diazo-reaction production operation safety is poor, is unfavorable for amplification production.
The master thesis (Wang Weizhong) of Institutes Of Technology Of Nanjing obtains 4- nitropyridine-through peroxidating, nitrification by pyridine
Then N- oxygen compound obtains 4- pyridone-N- oxygen compound by 4- nitropyridine-N- oxygen compound, finally restore 4- hydroxyl
Yl pyridines-N- oxygen compound obtains target product 4- pyridone, total recovery 45.5%.
The route steps are long, cumbersome, and quantity of three wastes is big, are unfavorable for environmental protection and industrialization amplification.
4-aminopyridine (12), also known as P-aminopyridine are the important intermediates of organic synthesis, medicine and Dyestuff synthesis,
It can be used for medical research, and clinic is used as potassium channel inhibitors, for treating neurological disease, such as myasthenia gravis；
Ligand etc. when also can be used as the substrate of molecular template reaction or carrying out Coordinative Chemistry research.
Document Tianjin Science & Engineering Univ journal 1999,15,80-82 and patent CN1807415, CN 106554306 and CN
107011255 using isonicotinic acid as starting material, prepares iso ethyl nicotinate through sulfuric acid catalysis esterification, then react with ammonia water and different cigarette is made
Sour amide obtains 4-aminopyridine, gross production rate 50% through Hofmann degradation under bromine water effect.
But the raw materials used isonicotinic acid price of the route is higher, and need to use the bromine of aggressive, industrialized production pair
Equipment and materials requires harsh and stringent to the larger needs of human injury safeguard procedures.
Document applied chemistry 2004,21 (5) and CN 1311185 are catalyzed using 4- cyanopyridine as raw material by Ni-Fe
Agent catalyzing hydrolysis obtains Pyrazinamide, then obtains 4-aminopyridine, yield 71% through Hofmann degradation.
Document chemical reagent 1998,20 (4): 240-241 and patent CN 1311185 are using pyridine as raw material, through hydrogen peroxide
N- pyridine-N-oxide is aoxidized to obtain, it then must be to nitro-N-pyridin oxide, then through through iron powder reducing or Raney Ni through mixed acid nitrification
Catalytic hydrogenating reduction prepares 4-aminopyridine, total recovery 65.5-68.1%.
This route nitration reaction wastewater flow rate is big, and when reduction need to consume a large amount of solvent, and last handling process is cumbersome, and generates
More waste water and waste residue.
Patent CN106243021 is using 4- chloropyridine as raw material, under catalyst (iron chloride, zinc chloride, copper chloride) effect
It in pressure is 0.8-3.0MPa with liquefied ammonia, temperature is to react 4-15 hours at 30-90 DEG C and prepare 4-aminopyridine.
4- dimethylamino pyridine (I3) is a kind of new and effective acylation catalyst, in alcohol, enol, amine, phenol, enol
It is widely used in the organic reactions such as ester, the acylation of isocyanide ester class and transesterification, alcohols etherificate.In addition, DMAP
It is also used as reverse phase phase transfer catalyst, is used for interfacial reaction.Due to its with reaction speed fast, mild condition, applicable
Solvent it is extensive and the advantages that product yield is higher, and it is unstable to be suitable for steric hindrance big alcohols and some pairs of acid
Hydroxyl, amine compound acylation reaction, DMAP is widely used in the fine chemistry industries such as medicine, pesticide, fragrance, petrochemical industry
Production field.
Document Henan chemical industry 1997,10,15-16 is using pyridine as raw material, through peroxidating, nitrification, chloro, amination and reduction five
Step reaction preparation 4- dimethylamino pyridine, total recovery reach 58.9%.This method reaction route is long, and the production cycle is long, and wastewater flow rate is big.
Document Chinese Journal of Pharmaceuticals 1993,24 (7): 321 using pyridine and thionyl chloride as raw material, and intermediate is first made
4- (4- pyridyl group) pyridinium chloride hydrochloride, then reacted with dimethylamine or dimethylformamide and generate 4-dimethylaminopyridine.This
Method temperature requirement is high, total recovery is low.
Patent CN103787963A is using 4- cyanopyridine as raw material, and quaternary ammonium acrylate, then reacts with aminated reagent
Prepare 4-dimethylaminopyridine.But raw materials used price is higher, is unfavorable for cost control, is unsuitable for large-scale industry metaplasia
It produces.
In addition, the bromo- 4- pyridone (I5) of 3- chloro-4-hydroxyl pyridine (I4), 3-, the chloro- 4-aminopyridine of 3- (I6), 3-
Bromo- 4-aminopyridine (I7), the chloro- 4- pyridone (I8) of 3,5- bis-, the bromo- 4- pyridone (I9) of 3,5- bis-, the chloro- 4- of 3,5- bis-
Aminopyridine (I10) and 3, bis- bromo- 4-aminopyridine (I11) of 5- is important pyridine derivate, wherein 3,5- bis- chloro- 4- amino
Pyridine (I10) is the key intermediate for preparing roflumilast.
Patent US5935978 prepares 3,5- bis- through chlorination using 4-aminopyridine as raw material, using hydrochloric acid, hydrogen peroxide
Chloro- 4-aminopyridine.Raw material 4-aminopyridine price is high, and 4-aminopyridine cloud density is high, is easily oxidised, is easy to generate
Thick by-product, this method are unsuitable for industrialized production.
In conclusion there are complex process, cost of material height, yield for the preparation method of pyridine derivate in the prior art
It is low, be unfavorable for environmental protection and the problems such as industrialized production.Therefore, a green, the 4- pyridone of low cost, 4- amino pyrrole are established
Pyridine, 4-dimethylaminopyridine, 3- chloro-4-hydroxyl pyridine, the bromo- 4- pyridone of 3-, the chloro- 4-aminopyridine of 3-, the bromo- 4- amino of 3-
Pyridine, the chloro- 4- pyridone of 3,5- bis-, the bromo- 4- pyridone of 3,5- bis-, the chloro- 4-aminopyridine of 3,5- bis- and the bromo- 4- of 3,5- bis-
The general preparative methods of aminopyridine, exploitation and industrialized production for drug downstream and chemical products have important meaning
Justice.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of preparation method of pyridine derivate, and this method is easy to operate,
Mild condition, process flow is short, and wastewater flow rate is low, environmentally protective, at low cost, high income.
Technical solution of the present invention is as follows:
A kind of preparation method of pyridine derivate, step include:
(1) halogenating reaction: in the presence of suitable solvent A, acid binding agent or without acid binding agent, piperidin-4-one hydrochloride and one
Quantitative halogenating agent obtains 3,5- dihalo piperidin-4-one, 3,3,5- tri- halopiperidine -4- ketone or 3 through halogenating reaction, and 3,
5,5- tetra- halopiperidine -4- ketone, after the reaction was completed, filtering are distilled to recover solvent, and residue is directly used in next without distillation
Walk elimination reaction；
(2) elimination reaction: in suitable solvent B, 3,5- dihalo piperidin-4-one, 3,3,5- tri- obtained by step (1)
Halopiperidine -4- ketone or 3,3,5,5- tetra- halopiperidine -4- ketone and alkaline reagent effect, obtain corresponding pyridine through elimination reaction and spread out
Biology I 1 to I 11.
I 1 to I 11 structural formula is as follows:
According to the method for the present invention, preferred processing condition and amount ratio are as follows in each step:
Preferably, solvent A described in step (1) be methylene chloride, chloroform, carbon tetrachloride, 1,2- methylene chloride,
One or a combination set of n-hexane, hexamethylene, petroleum ether, tetrahydrofuran, benzene, toluene are solvent-free, the solvent A and piperidines-
The mass ratio of 4- keto hydrochloride is (5~15): 1.
Preferably, acid binding agent described in step (1) is potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, hydrogen
The molar ratio of one or a combination set of potassium oxide, calcium hydroxide, the acid binding agent and piperidin-4-one hydrochloride is (0.0~2.0):
1。
Preferably, halogenating agent described in step (1) be chlorine, N- chlorosuccinimide, hydrochloric acid-sodium hypochlorite,
One or a combination set of hydrochloric acid-hydrogen peroxide, bromine, N- bromo-succinimide, hydrobromic acid-sodium bromate, hydrobromic acid-hydrogen peroxide, halogen
For reagent dosage depending on target halogenated product, the molar ratio of the halogenating agent and piperidin-4-one hydrochloride is (2.0
~5.0): 1, further preferred molar ratio is (2.1~4.5): 1.
Preferably, halogenating reaction temperature is 10~80 DEG C in step (1), is reacted 2~8 hours.Further preferably, halogenated anti-
Answering temperature is 40~60 DEG C, is reacted 4~6 hours.
Preferably, solvent B described in step (2) is methylene chloride, chloroform, methanol, ethyl alcohol, tetrahydrofuran, 2-
One or a combination set of methyltetrahydrofuran is solvent-free, the solvent B and 3,5- dihalo piperidin-4-one, 3,3,5- tri- halogen
Weight ratio for tetra- halopiperidine -4- ketone of piperidin-4-one or 3,3,5,5- is (5~15): 1.
Preferably, alkaline reagent described in step (2) be inorganic base, certain density ammonium hydroxide or ammonia alcoholic solution, it is certain dense
The dimethylamine agueous solution or dimethylamine alcoholic solution of degree；The inorganic base be potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus,
Sodium hydroxide, potassium hydroxide, calcium hydroxide；The alkaline reagent and 3,5- dihalo piperidin-4-one, the halogenated piperazine of 3,3,5- tri-
Pyridine -4- ketone or 3, the molar ratios of 3,5,5- tetra- halopiperidine -4- ketone are (2.0~5.0): 1, further preferred molar ratio is
(2.5~4.0): 1.It is further preferred that the mass concentration of the ammonium hydroxide or ammonia alcoholic solution is 10~30%；The diformazan
The mass concentration of amine aqueous solution or dimethylamine alcoholic solution is 7~30%.
Preferably, elimination reaction temperature is 10~80 DEG C in step (2), is reacted 2~8 hours.Further preferably, it eliminates anti-
Answering temperature is 30~50 DEG C, is reacted 3~5 hours.
Method of the invention is described as following synthetic route 12:
Wherein, X Br, Cl, H；B is OH, NH2、NMe2。
Technical characterstic of the invention and the utility model has the advantages that
1, the present invention obtains a series of pyridines through halogenating reaction and elimination reaction and spreads out using piperidin-4-one hydrochloride as raw material
Biology.Raw materials used cheap and easy to get, route is brief, and quantity of three wastes is few, is conducive to the industrialized production of safety and environmental protection.
2, the present invention obtains 3,5- dihalo piperazine through halogenating reaction with piperidin-4-one hydrochloride and the halogenating agent of specific quantity
Pyridine -4- ketone, 3,3,5- tri- halopiperidine -4- ketone or 3,3,5,5- tetra- halopiperidine -4- ketone are controlled according to the dosage of halogenating agent
Halogenated number obtains corresponding halogenated product, and reaction selectivity is high, and high income can reach 88.6% or more.
3, the present invention is using different types of alkaline reagent and preferred dosage, respectively with 3,5- dihalo piperidin-4-one,
It is respectively hydroxyl, ammonia that tri- halopiperidine -4- ketone of 3,3,5- or tetra- halopiperidine -4- ketone of 3,3,5,5-, which obtain 4- through elimination reaction,
The pyridine derivate of base or dimethylamino, reaction selectivity is high, and is easy to carry out, and prepares convenient for the seriation of product.
4, operation of the present invention is easy, and mild condition, process flow is short, and wastewater flow rate is low, environmentally protective, at low cost, is conducive to
The green industrialized production of the pyridine derivate.
Specific embodiment
Embodiments discussed below and comparative example have carried out detailed complete explanation to technical solution of the present invention, but originally
Invention is not limited only to following embodiment.Based on the embodiment of the present invention, anyone skilled in the art combination the technical program is spread out
Any scheme or embodiment for not having creativeness born, or any implementation for not having creativeness based on the present invention program
The variation of sequence, all belongs to the scope of protection of the present invention.
The raw materials used piperidin-4-one hydrochloride of embodiment provides or refers to prior art system by Jinan Rui Hui Pharma Inc.
Standby, remaining raw materials and reagents is commercial product." % " described in embodiment is weight percentage, except special instruction.
The preparation of embodiment 1:3,5- dichloro piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of chloroforms, 27.1 gram (0.2
Mole) piperidin-4-one hydrochloride, be passed through chlorine between 40-45 DEG C, it is common enter 32.0 grams of chlorine, 40-45 DEG C to be stirred to react 5 small
When, it is cooled to 20-25 DEG C, nitrogen blows the hydrogen chloride gas for catching up with remaining chlorine and by-product, blows and catches up with 2 hours, and 50 grams of water are added, and uses
It is 7-8 that 20% aqueous sodium carbonate, which adjusts pH value, is layered, and organic phase is washed 1 time with 20 grams of saturated sodium-chloride water solutions, is layered,
It is distilled to recover solvent, obtains 39.9 grams of light yellow liquids 3,5- dichloro piperidin-4-one is directly used in related elimination reaction.
The preparation of embodiment 2:3,5- dibromo piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of chloroforms, 13.6 gram (0.1
Mole) piperidin-4-one hydrochloride, 41.0 grams of (0.2 mole) 40% hydrobromic acids, in 30-35 DEG C of 24.0 (0.21 moles) of dropwise addition
30% hydrogen peroxide, drop finishes within about 2 hours, and 30-35 DEG C is stirred to react 3 hours, and 50 grams of water are added, and is adjusted with 20% aqueous sodium carbonate
PH value is 7-8, and layering, organic phase is washed 1 time with 20 grams of saturated sodium-chloride water solutions, is layered, and is distilled to recover solvent, obtains 29.2
Gram yellow liquid 3,5- dibromo piperidin-4-one are directly used in related elimination reaction.
The preparation of embodiment 3:3,3,5- trichlorine piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of methylene chloride, 27.1 grams
(0.2 mole) piperidin-4-one hydrochloride, 43.0 grams of (0.41 mole) 35% hydrochloric acid, in 30-35 DEG C of 74.0 (0.65 moles) of dropwise addition
30% hydrogen peroxide, drop finishes within about 3 hours, and hereafter, 40-45 DEG C is stirred to react 3 hours, is cooled to 20-25 DEG C, and nitrogen, which is blown, catches up with residual chlorine
Gas and hydrogen chloride gas 1 hour, are added 50 grams of water, and adjusting pH value with 20% aqueous sodium carbonate is 7-8, and layering, organic phase is used
20 grams of saturated sodium-chloride water solutions wash 1 time, and layering is distilled to recover solvent, obtains 47.4 grams of yellow liquids, 3,3,5- trichlorine piperazine
Pyridine -4- ketone, is directly used in related elimination reaction.
The preparation of embodiment 4:3,3,5- tribromo piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of methylene chloride, 13.6 grams
(0.1 mole) piperidin-4-one hydrochloride, 61.0 grams of (0.3 mole) 40% hydrobromic acids, being added dropwise 36.5 in 30-35 DEG C, (0.32 rubs
You) 30% hydrogen peroxide, drop finishes within about 2 hours, and 30-35 DEG C is stirred to react 3 hours, 50 grams of water is added, with 20% aqueous sodium carbonate
Adjusting pH value is 7-8, is layered, and organic phase is washed 1 time with 20 grams of saturated sodium-chloride water solutions, is layered, and is distilled to recover solvent, obtains
37.1 grams of 3,3,5- tribromo piperidin-4-ones of yellow liquid, are directly used in related elimination reaction.
The preparation of embodiment 5:3,3,5,5- tetrachloro piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of methylene chloride, 27.1 grams
(0.2 mole) piperidin-4-one hydrochloride, 75 gram of 35% hydrochloric acid, in 30-35 DEG C of 100.0 (0.88 mole) 30% hydrogen peroxide of dropwise addition,
Drop finishes within about 3 hours, and hereafter, 40-45 DEG C is stirred to react 3 hours, is cooled to 20-25 DEG C, and nitrogen, which is blown, catches up with remaining chlorine and hydrogen chloride
Gas blows and catches up with 1 hour, and 50 grams of water are added, and adjusting pH value with 20% aqueous sodium carbonate is 7-8, layering, and organic phase is full with 20 grams
It is washed 1 time with sodium-chloride water solution, layering is distilled to recover solvent, obtains 55.0 grams of yellow liquids, 3,3,5,5- tetra- Chloperastine -4-
Ketone is directly used in related elimination reaction.
The preparation of embodiment 6:3,3,5,5- tetrabromo piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of methylene chloride, 13.6 grams
(0.1 mole) piperidin-4-one hydrochloride, 85.0 grams of (0.4 mole) 40% hydrobromic acids, being added dropwise 50.0 in 30-35 DEG C, (0.44 rubs
You) 30% hydrogen peroxide, drop finishes within about 2 hours, and 30-35 DEG C is stirred to react 3 hours, 50 grams of water is added, with 20% aqueous sodium carbonate
Adjusting pH value is 7-8, is layered, and organic phase is washed 1 time with 20 grams of saturated sodium-chloride water solutions, is layered, and is distilled to recover solvent, obtains
45.0 grams of 3,3,5,5- tetrabromo piperidin-4-ones of yellow liquid, are directly used in related elimination reaction.
The preparation of embodiment 7:4- pyridone
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 100 grams of tetrahydrofurans, 10.2 grams
1 gained 3,5- dichloro piperidin-4-one of (0.05 mole) embodiment, 10.0 grams of potassium carbonate, 40-45 DEG C is stirred to react 3 hours, cooling
To 20-25 DEG C, filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover solvent, is obtained 4.43 grams of white solid 4-
Pyridone, yield 93.3% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.1%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.26(d,2H),6.86(d,2H),5.36(s,1H)。
The preparation of embodiment 8:4- aminopyridine
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 100 grams of methylene chloride, 14.7 grams
2 gained 3,5- dibromo piperidin-4-one of (0.05 mole) embodiment, 20.0 grams of (0.2 mole) 17% ammonium hydroxide, 40-45 DEG C of stirring are anti-
It answers 4 hours, is cooled to 20-25 DEG C, layering, water layer is extracted with dichloromethane 2 times, 20 grams every time, merges organic phase, is distilled to recover
Solvent obtains 4.26 grams of 4-aminopyridines, yield 90.6% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 98.6%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.37(d,2H),7.01(d,2H),4.23(br,2H)。
The preparation of embodiment 9:4- dimethylamino naphthyridine
Into 500 milliliters of autoclave pressures, 100 grams of methanol, 14.7 grams of 2 gained 3,5- dibromo piperazines of (0.05 mole) embodiment are added
Pyridine -4- ketone, 30 grams of (0.2 mole) 30% dimethylamine methanol solutions, 40-45 DEG C is stirred to react 4 hours, is cooled to 20-25 DEG C, mistake
Filter, filter cake (dimethylamine hydrobromate) are washed with 20 grams of solvents, merging filtrate, are distilled to recover solvent, are obtained 5.47 grams of 4- diformazans
Aminopyridine, yield 89.7% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 98.9%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.14(d,2H),6.98(d,2H),2.62(s,6H)。
The preparation of embodiment 10:3- chloro-4-hydroxyl pyridine
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 130 grams of methanol, 12.0 gram (0.05
Mole) 3,3, the 5- trichlorine piperidin-4-ones of gained of embodiment 3,4.1 grams of sodium hydroxides, 40-45 DEG C is stirred to react 2 hours, is cooled to
20-25 DEG C, filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover solvent, it is chloro- to obtain 5.74 grams of white solid 3-
4- pyridone, yield 88.6% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.3%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):9.93(s,1H),8.63(d,1H),8.11(d,1H),6.18(s,1H)。
The preparation of the bromo- 4- pyridone of embodiment 11:3-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 130 grams of chloroforms, 18.6 gram (0.05
Mole) 3,3, the 5- tribromo piperidin-4-ones of gained of embodiment 4,17.5 grams of potassium carbonate, 35-40 DEG C is stirred to react 2 hours, is cooled to
20-25 DEG C, filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover solvent, it is bromo- to obtain 7.77 grams of white solid 3-
4- pyridone, yield 89.3% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.1%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.33(s,1H),8.20(d,1H),6.93(d,1H),5.36(s,1H)。
The preparation of the chloro- 4-aminopyridine of embodiment 12:3-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 100 grams of methylene chloride, 12.0 grams
33,3,5- trichlorine piperidin-4-ones of gained of (0.05 mole) embodiment, 30.0 grams of (0.3 mole) 17% ammonium hydroxide, 35-40 DEG C of stirring
Reaction 4 hours is cooled to 20-25 DEG C, and layering, water layer is extracted with dichloromethane 2 times, 20 grams every time, merges organic phase, distills back
Solvent is received, 5.75 grams of chloro- 4-aminopyridines of 3-, yield 89.5% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity are obtained
98.9%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.65(s,1H),8.61(d,1H),7.13(d,1H),4.14(br,2H)。
The preparation of the bromo- 4-aminopyridine of embodiment 13:3-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 100 grams of methylene chloride, 18.6 grams
43,3,5- tribromo piperidin-4-ones of gained of (0.05 mole) embodiment, 30.0 grams of (0.3 mole) 17% ammonium hydroxide, 35-40 DEG C of stirring
Reaction 4 hours is cooled to 20-25 DEG C, and layering, water layer is extracted with dichloromethane 2 times, 20 grams every time, merges organic phase, distills back
Solvent is received, 7.8 grams of bromo- 4-aminopyridines of 3-, yield 90.2% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity are obtained
99.1%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.14(s,1H),7.96(d,1H),6.68(d,1H),4.43(br,2H)。
The preparation of the chloro- 4- pyridone of embodiment 14:3,5- bis-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 130 grams of methanol, 13.7 gram (0.05
Mole) 3,3,5, the 5- tetrachloro piperidin-4-ones of gained of embodiment 5,16.6 grams of potassium carbonate, 50-55 DEG C is stirred to react 3 hours, cooling
To 20-25 DEG C, filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover solvent, is obtained 7.47 grams of white solids 3,
The chloro- 4- pyridone of 5- bis-, yield 91.1% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.1%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.62(s,2H),5.76(s,1H)。
The preparation of the bromo- 4- pyridone of embodiment 15:3,5- bis-
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 130 grams of tetrahydrofurans, 22.6 grams
63,3,5,5- tetrabromo piperidin-4-ones of gained of (0.05 mole) embodiment, 16.6 grams of potassium carbonate, 50-55 DEG C is stirred to react 3 hours,
It is cooled to 20-25 DEG C, filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover solvent, and it is solid to obtain 11.5 grams of whites
Body 3, the bromo- 4- pyridone of 5- bis-, yield 90.9% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.2%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.56(s,2H),5.36(s,1H)。
The preparation of the chloro- 4-aminopyridine of embodiment 16:3,5- bis-
Into 500 milliliters of autoclave pressures, 130 grams of methanol, 13.7 grams of 5 gained 3,3,5,5- tetra- of (0.05 mole) embodiment are added
Chloperastine -4- ketone, 35.0 grams of (0.2 mole) 10% methanolic ammonia solutions, 40-45 DEG C is stirred to react 4 hours, is cooled to 20-25 DEG C,
Filtering, filter cake are washed with 20 grams of solvents, merging filtrate, are distilled to recover solvent, are obtained 7.31 grams of white solids 3, the chloro- 4- ammonia of 5- bis-
Yl pyridines, yield 89.7% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.3%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.71(s,2H),4.35(br,2H)。
The preparation of the bromo- 4-aminopyridine of embodiment 17:3,5- bis-
Into 500 milliliters of autoclave pressures, 130 grams of methanol, 22.6 grams of 6 gained 3,3,5,5- tetra- of (0.05 mole) embodiment are added
Bromine piperidin-4-one, 34.0 grams of (0.2 mole) 10% methanolic ammonia solutions, 45-50 DEG C is stirred to react 3 hours, is cooled to 20-25 DEG C,
Filtering, filter cake are washed with 20 grams of solvents, merging filtrate, are distilled to recover solvent, are obtained 11.5 grams of white solids 3, the bromo- 4- ammonia of 5- bis-
Yl pyridines, yield 91.3% (yield is in terms of piperidin-4-one hydrochloride), liquid phase purity 99.0%.
The nuclear magnetic data of product is as follows:
1H NMR(CDCl3,δ,ppm):8.12(s,2H),4.39(br,2H)。
The preparation of comparative example 1:3,5- dibromo piperidin-4-one
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 200 grams of chloroforms, 13.6 gram (0.1
Mole) piperidin-4-one hydrochloride, 44.5 grams of (0.22 mole) 40% hydrobromic acids, in 30-35 DEG C of 25.0 (0.22 moles) of dropwise addition
30% hydrogen peroxide, drop finishes within about 2 hours, and 30-35 DEG C is stirred to react 3 hours, and 50 grams of water are added, and is adjusted with 20% aqueous sodium carbonate
PH value is 7-8, and layering, organic phase is washed 1 time with 20 grams of saturated sodium-chloride water solutions, is layered, and is distilled to recover solvent, obtains 32.3
Gram yellow liquid, 3,5- dibromo piperidin-4-ones and 3, the gas phase area ratio of 3,5- tribromo piperidin-4-ones are 81.3%:18.2%,
Contain 18.2% three bromo by-products, it is difficult to by distillation and recrystallization purifying, be unfavorable for obtaining for related elimination reaction
Product.
The preparation of comparative example 2:4- pyridone
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, 100 grams of tetrahydrofurans obtain
32.3 grams of 1 gained 3,5- dibromo piperidin-4-ones and 3 of comparative example, 3,5- tribromo piperidin-4-one mixtures, 20.0 grams of potassium carbonate,
40-45 DEG C is stirred to react 3 hours, is cooled to 20-25 DEG C, and filtering, filter cake is washed with 20 grams of solvents, merging filtrate, is distilled to recover
Solvent, obtains 10.9 grams of white solids, and the analysis of liquid phase external standard method wherein contains 7.6 grams of 4- pyridones, the bromo- 4- hydroxyl of 3.3 grams of 3-
Yl pyridines are recrystallized to give 5.2 grams of 4- pyridones using n-hexane and ethyl acetate (volume ratio 3:1) twice, and two steps are always received
Rate 54.7% (yield is in terms of the piperidin-4-one hydrochloride used in the comparative example 1), liquid phase purity 98.3%.
The preparation of comparative example 3:4- dimethylamino naphthyridine
Into 500 milliliters of autoclave pressures, 100 grams of methanol, 14.7 grams of 2 gained 3,5- dibromo piperazines of (0.05 mole) embodiment are added
Pyridine -4- ketone, 15 grams of (0.1 mole) 30% dimethylamine methanol solutions, 40-45 DEG C is stirred to react 4 hours, is cooled to 20-25 DEG C, mistake
Filter, filter cake (dimethylamine hydrobromate) are washed with 20 grams of solvents, merging filtrate, are distilled to recover solvent, are obtained 5.12 grams of solids, liquid
The analysis of phase external standard method contains 3.41 grams of 4-dimethylaminopyridine, and 1.26 grams of 4- pyridones need to be further purified.
Purification process: 5.12 grams of solid crude products of gained are dissolved in 100 grams of methylene chloride, 10 gram of 15% sodium hydroxide water is added
Solution stirs 1 hour at room temperature, layering, washs organic phase with 10 grams of saturated sodium-chloride water solutions, 2.0 grams of anhydrous sodium sulfates are dry
Dry organic phase 4 hours, filtering, filtrate are concentrated to get 3.28 grams of 4-dimethylaminopyridine, yield 53.8%, liquid phase purity
98.5%.
From the above comparative example 1-3:
The dosage of halogenating agent and alkaline reagent is committed step of the invention, and comparative example 1 shows to control halogenating agent
Dosage, it is extremely important for controlling halogenated degree, if halogenating agent dosage is insufficient, obtain 3- bromine piperidin-4-one and 3,5 dibromos
Piperidin-4-one mixture；Halogenating agent dosage is more, obtains 3,3,5- tribromo piperidin-4-ones and 3, the mixing of 5 dibromo piperidin-4-ones
Object is difficult to purify, and is unfavorable for directly carrying out the elimination reaction of step (2).Elimination reaction product assay is low, needs repeatedly pure
Change, yield is low.With specific reference to comparative example 2.Comparative example 3 shows that alkaline reagent used in step (2) elimination reaction wants enough, every elimination
One hydrogen halides needs 1 equivalent alkaline reagent, and if alkaline reagent amount is insufficient, then by-product is more, needs special purification process, receives
Rate is low.
Claims (10)
1. a kind of preparation method of pyridine derivate, which is characterized in that step includes:
(1) halogenating reaction: in the presence of suitable solvent A, acid binding agent or without acid binding agent, piperidin-4-one hydrochloride and a certain amount of
Halogenating agent, obtain 3,5- dihalo piperidin-4-one, 3,3,5- tri- halopiperidine -4- ketone or 3,3,5,5- through halogenating reaction
Four halopiperidine -4- ketone, after the reaction was completed, filtering are distilled to recover solvent, and residue is directly used in and disappears in next step without distillation
Except reaction；
(2) elimination reaction: in suitable solvent B, by 3,5- dihalo piperidin-4-one obtained by step (1), 3,3,5- tri- halogenated
Piperidin-4-one or 3,3,5,5- tetra- halopiperidine -4- ketone and alkaline reagent effect, obtain corresponding pyridine derivate through elimination reaction
I 1 to I 11；
I 1 to I 11 structural formula is as follows:
2. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that molten described in step (1)
Agent A be methylene chloride, chloroform, carbon tetrachloride, 1,2- methylene chloride, n-hexane, hexamethylene, petroleum ether, tetrahydrofuran,
One or a combination set of benzene, toluene are solvent-free, and the mass ratio of the solvent A and piperidin-4-one hydrochloride is (5~15): 1.
3. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that step ties up acid described in (1)
Agent be one or a combination set of potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, it is described
The molar ratio of acid binding agent and piperidin-4-one hydrochloride is (0.0~2.0): 1.
4. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that halogen described in step (1)
It is chlorine, N- chlorosuccinimide, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, bromine, N- bromo succinyl Asia for reagent
One or a combination set of amine, hydrobromic acid-sodium bromate, hydrobromic acid-hydrogen peroxide, the dosage of halogenating agent according to target halogenated product and
Fixed, the molar ratio of the halogenating agent and piperidin-4-one hydrochloride is (2.0~5.0): 1.
5. a kind of preparation method of pyridine derivate as claimed in claim 4, which is characterized in that halogen described in step (1)
It is (2.1~4.5) for the molar ratio of reagent and piperidin-4-one hydrochloride: 1.
6. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that halogenating reaction in step (1)
Temperature is 10~80 DEG C, is reacted 2~8 hours；Further preferably, halogenating reaction temperature is 40~60 DEG C, is reacted 4~6 hours.
7. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that molten described in step (2)
Agent B is for one or a combination set of methylene chloride, chloroform, methanol, ethyl alcohol, tetrahydrofuran, 2- methyltetrahydrofuran or without molten
Agent, the solvent B and 3,5- dihalo piperidin-4-one, 3,3,5- tri- halopiperidine -4- ketone or 3,3,5,5- tetra- halopiperidines -
The weight ratio of 4- ketone is (5~15): 1.
8. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that alkalinity described in step (2)
Reagent is inorganic base, certain density ammonium hydroxide or ammonia alcoholic solution, certain density dimethylamine agueous solution or dimethylamine alcoholic solution；Institute
The inorganic base stated is potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, calcium hydroxide；The alkali
Property tetra- halopiperidine -4- ketone of reagent and 3,5- dihalo piperidin-4-one, tri- halopiperidine -4- ketone of 3,3,5- or 3,3,5,5-
Molar ratio is (2.0~5.0): 1；Preferably, the mass concentration of the ammonium hydroxide or ammonia alcoholic solution is 10~30%；Described two
The mass concentration of methylamine water solution or dimethylamine alcoholic solution is 7~30%.
9. a kind of preparation method of pyridine derivate as claimed in claim 8, which is characterized in that alkalinity described in step (2)
Reagent and 3,5- dihalo piperidin-4-one, tri- halopiperidine -4- ketone of 3,3,5- or tetra- halopiperidine -4- ketone of 3,3,5,5- rub
You are than being (2.5~4.0): 1.
10. a kind of preparation method of pyridine derivate as described in claim 1, which is characterized in that elimination reaction in step (2)
Temperature is 10~80 DEG C, is reacted 2~8 hours；Further preferably, elimination reaction temperature is 30~50 DEG C, is reacted 3~5 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 |
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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 |
| JP2003064011A (en) * | 2001-08-29 | 2003-03-05 | Dainippon Ink & Chem Inc | Method for producing 6-hydroxytetralin |
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