CN107253930A - A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 - Google Patents
A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 Download PDFInfo
- Publication number
- CN107253930A CN107253930A CN201710424075.6A CN201710424075A CN107253930A CN 107253930 A CN107253930 A CN 107253930A CN 201710424075 A CN201710424075 A CN 201710424075A CN 107253930 A CN107253930 A CN 107253930A
- Authority
- CN
- China
- Prior art keywords
- solvent
- reaction
- acid
- bromo
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to field of fine chemical, more particularly to a kind of preparation method of the aldehyde radical pyridine of 2 bromine 5.The present invention provides a kind of preparation method of the aldehyde radical pyridine of 2 bromine 5, comprises the following steps：1）The PMC of 2 chlorine 5 is subjected to bromination reaction under conditions of bromide reagent presence, the bromo methyl cycloheptapyridine of 2 bromine 5 is prepared；2）Under oxidising agent and alkali metal salt effect oxidation reaction is occurred into for the bromo methyl cycloheptapyridine of 2 bromine 5, the aldehyde radical pyridine of 2 bromine 5 is prepared.The preparation method of the aldehyde radical pyridine of 2 bromine 5 provided by the present invention is using the PMC of 2 chlorine 5 as raw material, the aldehyde radical pyridine of 2 bromine 5 is prepared by bromination and oxidation two-step reaction, technological operation is simple, reaction condition is gentle, safety, low raw-material cost, and reaction conversion ratio is high, high income, product is easy to extract, therefore it is more suitable for industrialization safety in production, with larger implementary value and economic results in society.
Description
Technical field
The present invention relates to field of fine chemical, the preparation method of more particularly to a kind of bromo- 5- aldehyde radicals pyridines of 2-.
Background technology
The bromo- 5- aldehyde radicals pyridines of 2- are a kind of important chemical intermediates, have in pharmacy, field of electronic materials and widely should
With value.
The synthetic method of the bromo- 5- aldehyde radicals pyridines of document report 2- is mostly using 2,5- dibromo pyridines as raw material, in ultralow temperature bar
Butyl lithium reaction is carried out under part, but temperature is whard to control, and there is potential safety hazard in severe reaction conditions, and cost of material is high, industry
Change operation difficulty big, and the technique can generate more isomers 2- aldehyde radicals -5- bromopyridines simultaneously, it is difficult to it is separated off.(Xiang Tan
University's natural science journal 31 (1), 53-28；2009).Also have using 2- amino -5- picolines as raw material, prepared through diazotising
The bromo- 5- picolines of 2-, then through N- bromo-succinimides bromination, hydrolysis prepare 2- bromo- 5- pyridine carboxaldehydes (chemical reagent,
28 (7), 433-434；2006), this method is not thorough due to reacting progress, and bromination, hydrolysing step yield only have 40%, conversion
The too low unsuitable industrial applications of rate.
The content of the invention
The shortcoming of prior art in view of the above, it is an object of the invention to provide a kind of bromo- 5- aldehyde radicals pyridines of 2-
Preparation method, for solving the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2-,
The structural formula of the bromo- 5- aldehyde radicals pyridines of 2- is as shown in formula III：
The preparation method comprises the following steps：
1) 2-vhloro-5-chloromethylpyridine is subjected to bromination reaction under conditions of bromide reagent presence, prepares 2- bromo-
5- bromo methyl cycloheptapyridines；
2) the bromo- 5- bromo methyl cycloheptapyridines of 2- are subjected to oxidation reaction in the presence of a base in 2- nitropropanes, preparation is obtained
Obtain 6- bromopyridine -3- formaldehyde.
In some embodiments of the invention, the step 1) in, the bromide reagent is selected from hydrogen bromide, bromine, dibromo
One or more combinations in glycolylurea, sodium bromide, tribromo oxygen phosphorus, N- bromo-succinimides.
In some embodiments of the invention, the step 1) in, the mol ratio of the brominated reagent and compound of formula I is
1~10：1.
In some embodiments of the invention, the step 1) in, the mol ratio of the brominated reagent and compound of formula I is
2~5：1.
In some embodiments of the invention, the step 1) in, the bromination reaction is carried out under conditions of acid is present,
One or more of combinations of the acid in formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, phosphoric acid.
In some embodiments of the invention, the step 1) in, when bromide reagent is selected from hydrogen bromide, bromine, bromination
Reaction is carried out under conditions of acid is present, the one kind or many of the acid in formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid
The combination planted.
In some embodiments of the invention, the step 1) in, when bromide reagent is selected from C5H6Br2N2O2 or N- bromo fourths
During imidodicarbonic diamide, bromination reaction is carried out under conditions of acid is present, and the acid is in trifluoroacetic acid, methanesulfonic acid, sulfuric acid, phosphoric acid
One or more of combinations.
In some embodiments of the invention, the step 1) in, the mass ratio of the sour consumption and compound of formula I is
0.5~10：1, preferably 1.5~7：1.
In some embodiments of the invention, the step 1) in, bromination reaction is carried out in the presence of a solvent, bromine
It is water and/or organic solvent to change the solvent used in reaction.
In some embodiments of the invention, the step 1) in, the organic solvent is selected from halogenated hydrocarbon solvent, alkane
One or more combinations in class solvent, esters solvent, alkyl benzene solvent, halo benzene kind solvent.
In some embodiments of the invention, the step 1) in, the organic solvent is selected from dichloromethane, two chloroethenes
One kind in alkane, ethyl acetate, butyl acetate, isopropyl acetate, toluene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro-benzenes, trichloro-benzenes
Or a variety of combinations.
In some embodiments of the invention, the step 1) in, when bromide reagent is selected from hydrogen bromide and/or sodium bromide
When, bromination reaction is carried out in the presence of a solvent, and the solvent is selected from water and/or organic solvent.
In some embodiments of the invention, the step 1) in, when bromide reagent is selected from bromine, C5H6Br2N2O2, tribromo
During one or more in oxygen phosphorus, N- bromo-succinimides, bromination reaction is carried out in the presence of a solvent, the solvent
Selected from organic solvent.
In some embodiments of the invention, the step 1) in, the usage amount of solvent can be Formulas I in bromination reaction
1~10 times of compound quality.
In some embodiments of the invention, the step 1) in, bromination reaction is carried out in enclosed system.
In some embodiments of the invention, the step 1) in, temperature of the bromination reaction in room temperature to reaction dissolvent boiling point
Carried out under the conditions of degree.
In some of the invention embodiments, the step 1) in, bromination reaction can be in 30-120 DEG C of temperature conditionss
It is lower to carry out.
In some of the invention embodiments, the step 1) in, bromination reaction can be in 80-110 DEG C of temperature conditionss
It is lower to carry out.
In some embodiments of the invention, the step 1) in, the post processing of bromination reaction comprises the following steps：It is cold
But, separation of solid and liquid, produces Formula II compound or its salt.
In some embodiments of the invention, the step 1) in, the post processing of bromination reaction comprises the following steps：Regulation
The pH of reaction system is 5-8, and Formula II compound is produced after organic phase concentration.
In some embodiments of the invention, the step 2) in, the oxidising agent is dimethyl sulfoxide.
In some embodiments of the invention, the step 2) in, the mol ratio of oxidising agent and Formula II compound is 0.9
~20：1.
In some of the invention embodiments, the step 2) in, the mol ratio of oxidising agent and Formula II compound for 1~
10：1.
In some embodiments of the invention, the step 2) in, alkali metal salt is selected from alkaline metal organic salt and/or alkali gold
Belong to inorganic salts.
In some embodiments of the invention, the step 2) in, the alkaline metal organic salt is selected from the organic sodium of alkali metal
Salt and/or alkali metal potassium salt.
In some embodiments of the invention, the step 2) in, the alkali metal inorganic salts are selected from the inorganic sodium of alkali metal
Salt and/or alkali metal inorganic potassium salt.
In some embodiments of the invention, the step 2) in, the alkaline metal organic salt is selected from sodium acetate, acetic acid
One or more combinations in potassium, sodium formate.
In some embodiments of the invention, the step 2) in, the alkali metal inorganic salts are selected from sodium carbonate, bicarbonate
One kind or many in sodium, potassium carbonate, saleratus, disodium-hydrogen, sodium dihydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, potassium phosphate
The combination planted.
In some of the invention embodiments, the step 2) in, the mol ratio of alkali metal salt and Formula II compound for 1~
3：1.
In some of the invention embodiments, the step 2) in, the mol ratio of alkali metal salt and Formula II compound for 1~
1.5：1.
In some embodiments of the invention, the step 2) in, oxidation reaction is carried out in the presence of a solvent, molten
One or more of the agent in ether solvent, esters solvent, halogenated hydrocarbon solvent, alkyl benzene solvent, halo benzene kind solvent
Combination.
In some embodiments of the invention, the step 2) in, the solvent is selected from ether, dipropyl ether, methyl- tert fourth
Base ether, ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate, ethylene carbonate, toluene, ethylbenzene, chlorobenzene, dichloro
One or more combinations in benzene.
In some of the invention embodiments, the step 2) in, oxidation reaction in bromide and/or iodide and/or
Iodine is carried out under conditions of existing.
In some embodiments of the invention, the step 2) in, the bromide is a kind of in sodium bromide, KBr
Or a variety of combinations.
In some embodiments of the invention, the step 2) in, the iodide are a kind of in sodium iodide, KI
Or a variety of combinations.
In some embodiments of the invention, the step 2) in, the bromide and/or iodide and/or iodine
The mass ratio of inventory and Formula II compound be 0.01%~50%：1.
In some embodiments of the invention, the step 2) in, the bromide and/or iodide and/or iodine
The mass ratio of inventory and Formula II compound be 0.05%~10%：1.
In some embodiments of the invention, the step 2) in, oxidation reaction is carried out under conditions of gas shield.
In some embodiments of the invention, the step 2) in, the gas for providing gas shield condition is nitrogen
And/or inert gas.
In some embodiments of the invention, the step 2) in, temperature of the oxidation reaction in room temperature to reaction dissolvent boiling point
Carried out under the conditions of degree.
In some embodiments of the invention, the step 2) in, oxidation reaction is entered under 30-120 DEG C of temperature conditionss
OK.
In some embodiments of the invention, the step 2) in, oxidation reaction is entered under 80-100 DEG C of temperature conditionss
OK.
In some embodiments of the invention, the step 2) in, the post processing of oxidation reaction comprises the following steps：It is de-
It is molten, add organic solvent and water is extracted, organic phase precipitation produces formula III compound.
Embodiment
Inventor is described by furtheing investigate there is provided a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of new 2-
The many disadvantages that preparation method is overcome in the existing method for preparing the bromo- 5- aldehyde radicals pyridines of 2- (including complex operation, are produced into
This height, conversion ratio are low, there is potential safety hazard etc. is unfavorable for industrialized production etc.), with technological operation is easy, cost of material is low,
High conversion rate, it is environmentally friendly, suitable for industrialization safety in production etc. beneficial effect, the present invention is completed on this basis.
The present invention provides a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2-, and the structural formula of the bromo- 5- aldehyde radicals pyridines of 2- is such as
Shown in formula III：
The preparation method comprises the following steps：2-vhloro-5-chloromethylpyridine (compound of formula I) is existed in bromide reagent
Under conditions of carry out bromination reaction, prepare the bromo- 5- bromo methyl cycloheptapyridines of 2- (Formula II compound), shown compound of formula I and formula
The structural formula of II compounds is as follows：
In preparation method provided by the present invention, the bromide reagent can be the various conventional bromide reagents in this area,
One kind or many in such as can be hydrogen bromide, bromine, C5H6Br2N2O2, sodium bromide, tribromo oxygen phosphorus, N- bromo-succinimides
The combination planted.In some of the invention preferred embodiments, during the bromide reagent preferably can be hydrogen bromide, tribromo oxygen phosphorus etc.
One or more combinations.Those skilled in the art may be selected suitable method and bromide reagent introduced into reaction system, for example,
Bromide reagent can be introduced directly into reaction system, reactant is introduced after can also bromide reagent be mixed with appropriate solvent
System.The usage amount of the bromide reagent relative to compound of formula I be typically equivalent or excess, for example, the brominated reagent with
The mol ratio of compound of formula I is 1~10：1, mol ratio preferably is 2~5：1.
In preparation method provided by the present invention, the bromination reaction can be carried out under conditions of acid is present, this area
Technical staff can select suitable acid according to the species of bromide reagent, so that bromide reagent has well in reaction system
Dissolubility, the acid can be the one or more in formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, phosphoric acid etc.
Combination.In the embodiment of the invention, when the bromide reagent is selected from hydrogen bromide and/or bromine, the acid can
To be one or more combinations in formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid etc..In another specific implementation of the present invention
In mode, when the bromide reagent is selected from C5H6Br2N2O2 and/or N- bromo-succinimides, the acid can be trifluoro second
One or more combinations in acid, methanesulfonic acid, sulfuric acid, phosphoric acid etc..The sour consumption and the mass ratio of compound of formula I can be with
For 0.5~10：1, or 1.5~7：1.
In preparation method provided by the present invention, the bromination reaction can be carried out under conditions of solvent-free presence,
It can carry out in the presence of a solvent, it is hereby achieved that preferably dispersion, those skilled in the art may be selected to close
The species and usage amount of suitable solvent are used for bromination reaction so that reaction raw materials can obtain fully dispersed in reaction system.
For example, the solvent used in bromination reaction can be water and/or organic solvent.In the embodiment of the invention, when
When bromide reagent is hydrogen bromide or sodium bromide, bromination reaction is carried out in the presence of a solvent, the solvent be selected from water and/or
Organic solvent；In another embodiment of the invention, when bromide reagent is selected from bromine, C5H6Br2N2O2, tribromo oxygen phosphorus, N- bromines
During for succimide, bromination reaction organic solvent or it is solvent-free under the conditions of carry out.The organic solvent can be halo
One or more combinations in varsol, alkane solvents, esters solvent, alkyl benzene solvent, halo benzene kind solvent etc.,
More specifically, the solvent can be dichloromethane, dichloroethanes, ethyl acetate, butyl acetate, isopropyl acetate, toluene, two
One or more combinations in toluene, trimethylbenzene, chlorobenzene, dichloro-benzenes, trichloro-benzenes etc..For another example solvent in bromination reaction
Usage amount can be 1~10 times of compound of formula I quality.
In preparation method provided by the present invention, the bromination reaction can be carried out in normal pressure system, can also be close
In closure system carry out, for example, when bromide reagent be hydrogen bromide when, bromination reaction can in autoclave confined reaction.
In preparation method provided by the present invention, bromination reaction can be under the temperature conditionss of room temperature to reaction dissolvent boiling point
Carry out, in the embodiment of the invention, reaction can be carried out under conditions of 30-120 DEG C, and reaction can also be in 80-
Carried out under conditions of 110 DEG C.Those skilled in the art can adjust the reaction time according to reaction process, for example, can pass through liquid phase
The methods such as chromatography judge the reaction process of bromination reaction, for another example the reaction time of bromination reaction can be 8-20 hours.
In preparation method provided by the present invention, it is anti-to bromination that suitable post-processing approach may be selected in those skilled in the art
The product answered is separated, for example, the post processing of bromination processing may include steps of：Cooling is (for example, reaction solution is dropped
Temperature), separation of solid and liquid produces Formula II compound or its salt；For another example the post processing of bromination reaction may include steps of：Adjust
The pH for saving reaction system is 5-8, and Formula II compound is produced after organic phase concentration.Suitable method may be selected in those skilled in the art
The pH value of reaction system is adjusted, it is, for example, possible to use the regulation such as sodium acid carbonate and/or sodium hydroxide (or their aqueous solution) is anti-
Answer the pH value of system.In the embodiment of the invention, appropriate organic solvent (example can also be added into reaction system
Such as, can add, can also be added after the pH of regulation reaction system before the pH of regulation reaction system), in order to react production
Thing is isolated and purified, and the organic solvent added in last handling process can be that halogenated hydrocarbon solvent, alkane solvents, esters are molten
One or more combinations in agent, alkyl benzene solvent, halo benzene kind solvent etc., more specifically, the organic solvent can be with
It is dichloromethane, dichloroethanes, ethyl acetate, butyl acetate, isopropyl acetate, toluene, dimethylbenzene, trimethylbenzene, chlorobenzene, dichloro
One or more combinations in benzene, trichloro-benzenes etc..
The preparation method of the bromo- 5- aldehyde radicals pyridines of 2- provided by the present invention can also include：By the bromo- 5- bromo methyl cycloheptapyridines of 2-
Under oxidising agent and alkali metal salt effect oxidation reaction occurs for (Formula II compound), prepares the bromo- 5- aldehyde radicals pyridine (formulas of 2-
III compounds).
In preparation method provided by the present invention, the oxidising agent can be dimethyl sulfoxide (DMSO), the oxidising agent phase
Equivalent either excess can be about for the consumption of Formula II compound, for example, oxidising agent and Formula II compound
Mol ratio can be 0.9~20：1, or 1~10：1.
In preparation method provided by the present invention, those skilled in the art may be selected the species of suitable alkali metal salt and make
Consumption is used for oxidation reaction, for example, the alkali metal salt can be alkaline metal organic salt and/or alkali metal inorganic salts etc., it is described
Alkaline metal organic salt can be alkali metal Organic Sodium Salt and/or alkali metal potassium salt etc., more specifically can be such as sodium acetate,
One or more combinations in potassium acetate, sodium formate etc., the alkali metal inorganic salts can be alkali metal inorganic sodium and/or
Alkali metal inorganic potassium salt etc., more specifically can be for example sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, disodium-hydrogen,
One or more combinations in sodium dihydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, potassium phosphate etc..It is embodied in the present invention one
In mode, the alkali metal salt is preferably disodium-hydrogen, potassium dihydrogen phosphate and sodium acid carbonate.The usage amount of the alkali metal salt
It is typically equivalent or excess relative to Formula II compound, alkali metal salt and the mol ratio of Formula II compound can be 1~3：
1, or 1.~1.5：1.
In preparation method provided by the present invention, oxidation reaction can be carried out in the presence of a solvent, this area skill
The species and usage amount that suitable solvent may be selected in art personnel are used for oxidation reaction so that reaction raw materials can be in reaction system
Obtain fully dispersed.For example, the solvent can be ether solvent, esters solvent, halogenated hydrocarbon solvent, alkyl benzene solvent,
One or more combinations in halo benzene kind solvent etc., more specifically, the solvent can be ether, dipropyl ether, methyl- tert
Butyl ether, ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate, ethylene carbonate, toluene, ethylbenzene, chlorobenzene, two
One or more combinations in chlorobenzene etc..For another example the usage amount of solvent can be Formula II compound quality in oxidation reaction
1~10 times.
In preparation method provided by the present invention, the oxidation reaction can be in bromide and/or iodide and/or simple substance
Iodine is carried out under conditions of existing, and the bromide can be one or more combinations in sodium bromide, KBr etc., the iodate
Thing can be such as sodium iodide, KI in one or more combination.The bromide and/or iodide and/or simple substance
The inventory of iodine can be 0.01%~50% with the mass ratio of Formula II compound：1, or 0.05%~10%：1.
In preparation method provided by the present invention, oxidation reaction can be carried out under conditions of gas shield, this area skill
Suitable gas may be selected to provide the condition of gas shield in art personnel, these gases generally not with the main thing in reaction system
Matter (for example, Formula II compound, formula III compound, 2- nitropropanes, alkali metal salt etc.) chemically reacts, for example, can be used for
The gas for providing gas shield condition can be one or more combinations in nitrogen, inert gas etc., the inert gas
Can be one or more combinations in helium, neon, argon gas, Krypton, xenon etc..
In preparation method provided by the present invention, oxidation reaction can be under the temperature conditionss of room temperature to reaction dissolvent boiling point
Carry out, in the embodiment of the invention, reaction can be carried out under 30-120 DEG C of temperature conditionss, can also be in 80-
Carried out under 100 DEG C of temperature conditionss.Those skilled in the art can adjust the reaction time according to reaction process, for example, can pass through
The methods such as liquid chromatography judge the reaction process of oxidation reaction, for another example the reaction time of oxidation reaction can be that 5-20 is small
When or 8-20 hours.
In preparation method provided by the present invention, the post processing of oxidation reaction may include steps of：Precipitation, addition has
Machine solvent and water are extracted, and organic phase precipitation produces formula III compound.Those skilled in the art may be selected suitable organic molten
Agent be used for extract formula III compound, such as can be dichloromethane, dichloroethanes, methyl tertiary butyl ether(MTBE) (MTBE) in one
Plant or a variety of combinations.
The preparation method of the bromo- 5- aldehyde radicals pyridines of 2- provided by the present invention is passed through using 2-vhloro-5-chloromethylpyridine as raw material
Bromination and oxidation two-step reaction prepare the bromo- 5- aldehyde radicals pyridines of 2-, and technological operation is simple, and reaction condition is gentle, safety, cost of material
It is cheap, and reaction conversion ratio is high, high income, product is easy to extract, therefore is more suitable for industrialization safety in production, with larger reality
Apply value and economic results in society.
Illustrate embodiments of the present invention below by way of specific instantiation, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also pass through specific realities different in addition
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints with application, without departing from
Various modifications or alterations are carried out under the spirit of the present invention.
It should be clear that in the following example not specifically dated process equipment or device using conventional equipment in the art or
Device.
In addition, it is to be understood that the one or more method and steps mentioned in the present invention do not repel before and after the combination step
There can also be other method step or other method step can also be inserted between the step of these are specifically mentioned, unless separately
It is described；It should also be understood that the combination annexation between the one or more equipment/devices mentioned in the present invention is not repelled
Can also have other equipment/device before and after the unit equipment/device or two equipment/devices specifically mentioning at these it
Between can also insert other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the numbering of various method steps is only
Differentiate the convenient tool of various method steps, rather than ordering or restriction enforceable model of the invention for limitation various method steps
Enclose, being altered or modified for its relativeness is of the invention enforceable when being also considered as in the case of without essence change technology contents
Category.
Embodiment 1
100g raw material 2-vhloro-5-chloromethylpyridines are taken, adds to Hastelloy autoclave, adds 25% hydrobromic acid vinegar
Acid solution 800g.Closed reactor, stirring is warming up to 100~110 DEG C.Reaction 10 hours.It is distilled to recover acetic acid.Residue is added
In DCM, adjusted with 10%NaOH liquid to pH=6-7.Divide liquid, gained organic phase, precipitation reclaims DCM.Residue is the bromo- 5- of 2-
Bromo methyl cycloheptapyridine, quality 139.7g, content 92%.
The bromo- 5- bromo methyl cycloheptapyridines of the above-mentioned 2- of 100g are taken, are dissolved in 300g toluene, 100g DMSO and 55g di(2-ethylhexyl)phosphates are added
Hydrogen sodium, 1g KBrs.Stirring, nitrogen is blasted under liquid level.It is warming up to 90~100 DEG C of reactions.Reaction 10 hours, reaction terminates
Afterwards, solvent, plus 100g water and 300g MTBE is distilled off, washing point liquid, gained organic phase is distilled to recover MTBE, residue 2-
Bromo- 5- aldehyde radicals pyridine 52.4g, purity about 95%.
Embodiment 2
100g raw material 2-vhloro-5-chloromethylpyridines are taken, adds to Hastelloy autoclave, adds 25% hydrobromic acid first
Acid solution 800g.Closed reactor, is warming up to 100~110 DEG C.Reaction 10 hours.It is distilled to recover formic acid.Residue adds DCM
In, adjusted with 10%NaOH liquid to pH=6-8.Divide liquid, gained organic phase, precipitation reclaims DCM.Residue is the bromo- 5- bromines of 2-
Picoline, quality 142.5g, content 88%.
The bromo- 5- bromo methyl cycloheptapyridines of the above-mentioned 2- of 100g are taken, are dissolved in 300g toluene, 100g DMSO and 55g phosphoric acid hydrogen is added
Disodium, 5g sodium iodides.Stirring, nitrogen is blasted under liquid level.It is warming up to 85~95 DEG C of reactions.Reaction 8 hours, after reaction terminates,
Solvent and part DMSO, cooling plus 100g water and 300g MTBE is distilled off, washing point liquid, gained organic phase is distilled to recover
The bromo- 5- aldehyde radicals pyridine 53g of MTBE, residue 2-, purity is more than 95%.
Embodiment 3
100g raw materials 2-vhloro-5-chloromethylpyridine and 300g dichloromethane are taken, is added in reaction bulb, 96% sulfuric acid is added
300g.80~85 DEG C are warming up to, C5H6Br2N2O2 260g is added in batches.Reaction 12 hours.Adjusted with 10%NaOH liquid to pH=
6-8, point liquid, gained organic phase, precipitation reclaims DCM.Residue is the bromo- 5- bromo methyl cycloheptapyridines of 2-, quality 136.4g, content
92%.
The bromo- 5- bromo methyl cycloheptapyridines of the above-mentioned 2- of 100g are taken, 500g DMSO and 55g disodium hydrogen phosphates are added, 5g KIs are stirred
Mix, nitrogen is blasted under liquid level.It is warming up to 90~100 DEG C of reactions.Reaction 8 hours, after reaction terminates, is distilled off DMSO, drops
Temperature plus 100g water and 300g MTBE, washing point liquid, gained organic phase are distilled to recover MTBE, the bromo- 5- aldehyde radicals pyridines of residue 2-
58.6g, purity is more than 95%.
Embodiment 4
Take 100g raw materials 2-vhloro-5-chloromethylpyridine and 200g toluene to add in reaction bulb, add 25% hydrobromic acid acetic acid
Solution 400g.It is warming up to 90~100 DEG C.Reaction 10 hours, precipitation.Residue is added in 200g DCM, is adjusted with 10%NaOH liquid
Save to pH=6-8.Divide liquid, gained organic phase, precipitation reclaims DCM.Residue is the bromo- 5- bromo methyl cycloheptapyridines of 2-, quality
144.9g, content 93%.
The bromo- 5- bromo methyl cycloheptapyridines of the above-mentioned 2- of 100g are taken, are dissolved in 300g toluene, 100g DMSO and 40g bicarbonates are added
Sodium, 5g KIs.Stirring, nitrogen is blasted under liquid level.It is warming up to 90~100 DEG C of reactions.Reaction 12 hours, after reaction terminates,
Solvent, cooling plus 100g water and 300g MTBE is distilled off, washing point liquid, gained organic phase is distilled to recover MTBE, residue 2-
Bromo- 5- aldehyde radicals pyridine 55g, purity about 94%.
Embodiment 5
100g raw material 2-vhloro-5-chloromethylpyridines are taken, benzotrifluoride 400g and methanesulfonic acid 150g is added, NBS is added
270g.It is warming up to 100~110 DEG C.Reaction 14 hours.Adjusted with 10%NaOH liquid to pH=6-8.Divide liquid, gained organic phase takes off
It is molten.Residue is the bromo- 5- bromo methyl cycloheptapyridines of 2-, quality 140.5g, content 89%.
The bromo- 5- bromo methyl cycloheptapyridines of the above-mentioned 2- of 100g are taken, are dissolved in 300g toluene, 50g DMSO and 55g phosphoric acid hydrogen two is added
Sodium, 5g elemental iodines.Stirring, nitrogen is blasted under liquid level.It is warming up to 90~100 DEG C of reactions.Reaction 12 hours, after reaction terminates,
Solvent, cooling plus 200g water and 200g dichloromethane is distilled off, washing point liquid, gained organic phase is distilled to recover solvent, remaining
The bromo- 5- aldehyde radicals pyridine 52.6g of thing 2-, purity about 95%.
In summary, the present invention effectively overcomes various shortcoming of the prior art and has high industrial utilization.
The above-described embodiments merely illustrate the principles and effects of the present invention, not for the limitation present invention.It is any ripe
Know the personage of this technology all can carry out modifications and changes under the spirit and scope without prejudice to the present invention to above-described embodiment.Cause
This, those of ordinary skill in the art is complete without departing from disclosed spirit and institute under technological thought such as
Into all equivalent modifications or change, should by the present invention claim be covered.
Claims (10)
1. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2-, the structural formula of the bromo- 5- aldehyde radicals pyridines of 2- is as shown in formula III：
The preparation method comprises the following steps：
1) 2-vhloro-5-chloromethylpyridine is subjected to bromination reaction under conditions of bromide reagent presence, prepares the bromo- 5- bromines of 2-
Picoline；
2) under oxidising agent and alkali metal salt effect oxidation reaction is occurred into for the bromo- 5- bromo methyl cycloheptapyridines of 2-, prepares 2- bromo-
5- aldehyde radical pyridines.
2. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 1, it is characterised in that also including following skill
One or more of art feature：
A1) the step 1) in, the bromide reagent is selected from hydrogen bromide, bromine, C5H6Br2N2O2, sodium bromide, tribromo oxygen phosphorus, N- bromines
For one or more combinations in succimide；
A2) the step 1) in, the mol ratio of the bromide reagent and compound of formula I is 1~10：1；
A3) the step 1) in, the bromination reaction is carried out under conditions of acid is present, and the acid is selected from formic acid, acetic acid, third
One or more of combinations in acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, phosphoric acid；
A4) the step 1) in, bromination reaction is carried out in the presence of a solvent, and the solvent used in bromination reaction is water
And/or organic solvent；
A5) the step 1) in, bromination reaction is carried out in enclosed system；
A6) the step 1) in, bromination reaction is carried out under the temperature conditionss of room temperature to reaction dissolvent boiling point；
A7) the step 1) in, the post processing of bromination reaction comprises the following steps：Cooling, separation of solid and liquid produces Formula II compound
Or its salt；
A8) the step 1) in, the post processing of bromination reaction comprises the following steps：The pH for adjusting reaction system is 5-8, organic phase
Formula II compound is produced after concentration.
3. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 2, it is characterised in that also including following skill
One or more of art feature：
B1) the step 1) in, the mol ratio of the brominated reagent and compound of formula I is 2~5：1；
B2) the step 1) in, when bromide reagent is selected from hydrogen bromide, bromine, bromination reaction is carried out under conditions of acid is present,
One or more combinations of the acid in formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid；When bromide reagent is selected from two
When bromine glycolylurea or N- bromo-succinimides, bromination reaction is carried out under conditions of acid is present, and the acid is selected from trifluoroacetic acid, first
One or more of combinations in sulfonic acid, sulfuric acid, phosphoric acid；
B3) the step 1) in, the mass ratio of the sour consumption and compound of formula I is 0.5~10：1, preferably 1.5~7：
1；
B4) the step 1) in, the organic solvent is selected from halogenated hydrocarbon solvent, alkane solvents, esters solvent, alkyl benzene
One or more combinations in solvent, halo benzene kind solvent；
B5) the step 1) in, when bromide reagent is selected from hydrogen bromide and/or sodium bromide, the bar that bromination reaction exists in solvent
Carried out under part, the solvent is selected from water and/or organic solvent；When bromide reagent is selected from bromine, C5H6Br2N2O2, tribromo oxygen phosphorus, N-
During one or more in bromo-succinimide, bromination reaction is carried out in the presence of a solvent, and the solvent, which is selected from, to be had
Machine solvent；
B6) the step 1) in, the usage amount of solvent is 1~10 times of compound of formula I quality in bromination reaction；
B7) the step 1) in, bromination reaction is carried out under 30-120 DEG C of temperature conditionss.
4. a kind of preparation method of 6- bromopyridines -3- formaldehyde as claimed in claim 3, it is characterised in that the step 1) in,
The organic solvent is selected from dichloromethane, dichloroethanes, ethyl acetate, butyl acetate, isopropyl acetate, toluene, dimethylbenzene, three
One or more combinations in toluene, chlorobenzene, dichloro-benzenes, trichloro-benzenes.
5. a kind of preparation method of 6- bromopyridines -3- formaldehyde as claimed in claim 3, it is characterised in that the step 1) in,
Bromination reaction is carried out under 80-110 DEG C of temperature conditionss.
6. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 1, it is characterised in that also including following skill
One or more of art feature：
C1) the step 2) in, the oxidising agent is dimethyl sulfoxide；
C2) the step 2) in, the mol ratio of oxidising agent and Formula II compound is 0.9~20：1；
C3) the step 2) in, alkali metal salt is selected from alkaline metal organic salt and/or alkali metal inorganic salts；
C4) the step 2) in, the mol ratio of alkali metal salt and Formula II compound is 1~3：1；
C5) the step 2) in, oxidation reaction is carried out in the presence of a solvent, solvent be selected from ether solvent, esters solvent,
One or more combinations in halogenated hydrocarbon solvent, alkyl benzene solvent, halo benzene kind solvent；
C6) the step 2) in, oxidation reaction is carried out under conditions of bromide and/or iodide and/or iodine are present；
C7) the step 2) in, the inventory of the bromide and/or iodide and/or iodine and the matter of Formula II compound
Amount is than being 0.01%~50%：1；
C8) the step 2) in, oxidation reaction is carried out under conditions of gas shield；
C9) the step 2) in, oxidation reaction is carried out under the temperature conditionss of room temperature to reaction dissolvent boiling point；
C10) the step 2) in, the post processing of oxidation reaction comprises the following steps：Precipitation, adds organic solvent and water is extracted
Take, organic phase precipitation produces formula III compound.
7. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 6, it is characterised in that also including following skill
One or more of art feature：
D1) the step 2) in, the mol ratio of oxidising agent and Formula II compound is 1~10：1；
D2) the step 2) in, the alkaline metal organic salt is selected from alkali metal Organic Sodium Salt and/or alkali metal potassium salt；
D3) the step 2) in, the alkali metal inorganic salts are selected from alkali metal inorganic sodium and/or alkali metal inorganic potassium salt；
D4) the step 2) in, the mol ratio of alkali metal salt and Formula II compound is 1~1.5：1；
D5) solvent is selected from ether, dipropyl ether, methyl tertiary butyl ether(MTBE), ethyl acetate, isopropyl acetate, dimethyl carbonate, carbon
One or more combinations in diethyl phthalate, ethylene carbonate, toluene, ethylbenzene, chlorobenzene, dichloro-benzenes；
D6) the step 2) in, bromide combination one or more in sodium bromide, KBr；
D7) the step 2) in, iodide combination one or more in sodium iodide, KI；
D8) the step 2) in, the inventory of the bromide and/or iodide and/or iodine and the matter of Formula II compound
Amount is than being 0.05%~10%：1；
D9) the step 2) in, the gas for providing gas shield condition is nitrogen and/or inert gas；
D10) the step 2) in, oxidation reaction is carried out under 30-120 DEG C of temperature conditionss.
8. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 7, it is characterised in that the step 2) in,
One or more combinations of the alkaline metal organic salt in sodium acetate, potassium acetate, sodium formate.
9. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 7, it is characterised in that the step 2) in,
The alkali metal inorganic salts are selected from sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, disodium-hydrogen, sodium dihydrogen phosphate, phosphorus
One or more combinations in sour sodium, potassium dihydrogen phosphate, potassium phosphate.
10. a kind of preparation method of the bromo- 5- aldehyde radicals pyridines of 2- as claimed in claim 7, it is characterised in that the step 2)
In, oxidation reaction is carried out under 80-100 DEG C of temperature conditionss.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710173405 | 2017-03-22 | ||
| CN2017101734059 | 2017-03-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107253930A true CN107253930A (en) | 2017-10-17 |
Family
ID=60024547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710424075.6A Pending CN107253930A (en) | 2017-03-22 | 2017-06-07 | A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107253930A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698497A (en) * | 2017-10-25 | 2018-02-16 | 衢州康鹏化学有限公司 | A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 |
| CN108033876A (en) * | 2017-12-20 | 2018-05-15 | 江汉大学 | A kind of preparation method of the bromo- 2- chlorobenzaldehydes of 5- |
-
2017
- 2017-06-07 CN CN201710424075.6A patent/CN107253930A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| FRANCIS MUTTERER: "Halogenated pyridines. V. Fluorinated and brominated pyridine compounds", 《HELVETICA CHIMICA ACTA》 * |
| 胡胜利，张合胜: "6 - 氯吡啶 - 3 - 甲醛的简便合成", 《湖北大学学报（自然科学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107698497A (en) * | 2017-10-25 | 2018-02-16 | 衢州康鹏化学有限公司 | A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 |
| CN108033876A (en) * | 2017-12-20 | 2018-05-15 | 江汉大学 | A kind of preparation method of the bromo- 2- chlorobenzaldehydes of 5- |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11718524B2 (en) | Method for manufacturing sulfur tetrafluoride | |
| EP2797873B1 (en) | Process for the production of choline hydroxide | |
| CN107253930A (en) | A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 | |
| CN106008175B (en) | A kind of production method of trifluomethoxybenzene | |
| CN116354876A (en) | Synthesis method of high-purity 2-chloro-5-methylpyridine | |
| CN110054642A (en) | A kind of preparation method of pair of chlorophenylboronic acid | |
| CN107056690A (en) | A kind of preparation method of the formaldehyde of 6 bromopyridine 3 | |
| CN104513198A (en) | 2-chloronicotinic acid synthetic method | |
| CN105198753B (en) | 2,2 ' is double（Trifluoromethoxy）The preparation method of 4,4 ' benzidines | |
| CN106336340B (en) | Synthesis method of o-bromobenzotrifluoride | |
| CN113582918B (en) | Method for preparing 2,3-dichloropyridine by chlorination | |
| CN106883259A (en) | A kind of preparation method of oleic acid methyl tin | |
| CN107641067A (en) | A kind of α positions bromination process of adjacent diketone | |
| JP6861060B2 (en) | Method for Producing 4,4'-Diiodot-3,3'-Dimethylbiphenyl | |
| CN105669505B (en) | A kind of preparation method of the sulphur two (dihydro cinnamic acid) of β, β ' two | |
| CN112830892A (en) | Synthesis method of pyridine-3-sulfonyl chloride | |
| CN105085439B (en) | A kind of preparation method of epoxiconazole intermediate | |
| CN104045521A (en) | Green synthesis technique of p-chloro-m-cresol | |
| CN104693164B (en) | A kind of preparation method of 2,2 difluoro methyl piperates | |
| CN107698497A (en) | A kind of preparation method of the aldehyde radical pyridine of 2 bromine 5 | |
| CN101301998A (en) | Method for synthesizing high-pure potash iodate | |
| CN109607480A (en) | A kind of waste hydrochloric acid edulcoration purification process in Sucralose chlorination reaction | |
| JPS6252730B2 (en) | ||
| CN107880069A (en) | A kind of trifluoromethyl（Trimethyl）The preparation method of silane | |
| CN102329235A (en) | Production process of p-nitrobenzaldehyde |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 2003-1 Building No. 200, 2891 Lane, Qilian Mountain South Road, Putuo District, Shanghai Applicant after: Shanghai Kangpeng Science and Technology Co., Ltd. Applicant after: Shanghai Wanshou Pharmaceutical Co., Ltd. Address before: 2003 2001 No. 200 Wuwei Road, Putuo District, Shanghai Applicant before: SHANGHAI KANGPENG TECHNOLOGY CO., LTD. Applicant before: Shanghai Wanshuo Chemistry Co., Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171017 |