CN105777623A - Method for preparing pyridine side chain methyl quaternary ammonium compound - Google Patents
Method for preparing pyridine side chain methyl quaternary ammonium compound Download PDFInfo
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- CN105777623A CN105777623A CN201610112222.1A CN201610112222A CN105777623A CN 105777623 A CN105777623 A CN 105777623A CN 201610112222 A CN201610112222 A CN 201610112222A CN 105777623 A CN105777623 A CN 105777623A
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
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Abstract
The invention relates to a method for preparing a pyridine side chain methyl quaternary ammonium compound.The method comprises the following steps that 1, in the presence of hydrosulphite and a catalyst, after a compound of the structure shown in the formula (4) and an aqueous solution of bromate are subjected to a two-phase bromination reaction, an organic phase is separated out; 2, the organic phase obtained in the step 1 and a compound of the structure shown in the formula (2) are subjected to a contact reaction, and a compound of the structure shown in the formula (1) is obtained, wherein in the formula (1), the formula (2), the formula (3) and the formula (4), R1 and R2 are independently selected from alkyl groups of C1-C8 respectively, and R3, R4 and R5 are independently selected from alkyl groups of C1-C4.The method has the advantages that operating conditions are simple, an adopted halogenate reagent is economical and easy to obtain, the utilization rate of bromine is high, corrosive gas and environmental harm are avoided, good selectivity is achieved, and the product yield is high, and the method is very suitable for large-scale industrial application.The formulas are shown in the description.
Description
Technical field
The present invention relates to the field of chemical synthesis, in particular it relates to a kind of pyridine side chain methyl quaternary ammonium salt
The preparation method of compound.
Background technology
[(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester is to prepare imidazolone type to remove
The important intermediate of grass agent imazamox.Existing preparation 5-bromomethyl-2,3-pyridinedicarboxylic acid esters
In the method for compound, frequently with NBS, CBrCl3、CuBr2、Br-/Br2As brominated reagent, adding
Carry out bromination under conditions of heat or illumination, use above method to exist reaction yield is low, complex operation,
Or use expensive brominated reagent, the simultaneously utilization rate of major part brominated reagent on the low side, it is easily generated
Corrosive hydrogen bromide gas, is unfavorable for industrialized production.
The known method many employings bromine preparing 5-bromomethyl-2,3-pyridinedicarboxylic acid ester type compound or
N-bromosuccinimide (NBS) is bromide reagent, such as EP0548532A1, US5288866A
In disclose employing NBS as bromide reagent, chlorobenzene is solvent, azodiisobutyronitrile (AIBN) make
Method for initiator carries out the bromination of pyridine side chain 5-position methyl.WO2010055139A1 discloses
Using with bromine as bromide reagent, azodiisobutyronitrile is initiator, with chloroform as solvent, uses even
The method that nitrogen isobutyl cyanogen causes carries out the bromination of pyridine side chain 5-position methyl.The shortcoming of above method is to adopt
Pyridine side chain methyl quaternary ammonium salt compounds, course of reaction is prepared as brominated reagent by NBS or bromine
In need to carry out in anhydrous system, the expensive raw material price simultaneously used, operation complexity, bromine react
The hydrogen bromide gas corrosive equipment of release, technique quantity of three wastes is big, and industrial operation is the most difficult.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of pyridine side chain methyl quaternary ammonium salt compounds,
The method has that operating condition halogenating agent simple, used is economical and easily available, bromine utilization rate is high, corrosion-free
Property gas, without environmental hazard, selectively good and product yield relatively advantages of higher, be highly suitable for advising greatly
Mould industrialized production.
To achieve these goals, the present invention provides a kind of pyridine side chain methyl quaternary ammonium salt compounds
Preparation method, described pyridine side chain methyl quaternary ammonium salt compounds is the compound of structure shown in formula (1),
Wherein, the method comprises the steps:
(1) in the presence of bisulfites and catalyst, by compound and the bromine of structure shown in formula (4)
The aqueous solution of hydrochlorate carries out after two-phase bromination reaction obtains the compound of structure shown in formula (3), isolating
Organic phase；
(2) compound of the organic phase obtained in step (1) with structure shown in formula (2) is connect
Touch reaction, obtain the compound of structure shown in formula (1)；
Wherein, in formula (1), formula (2), formula (3) and formula (4), R1And R2The most independent
Ground is selected from C1-C8Alkyl, R3、R4And R5It is each independently selected from C1-C4Alkyl.
By technique scheme, employing bromate is as bromide reagent, than traditional bromine, NBS
As bromide reagent, reaction condition milder, reduce cost of material, simultaneously also without anhydrous
Under the conditions of react, the requirement to equipment is greatly reduced.Corrosive HBr gas will not be produced
Body, the most just can avoid equipment corrosion, pollutes the problems such as environment, it is simple to industrialized production.
Other features and advantages of the present invention will give specifically in detailed description of the invention part subsequently
Bright.
Detailed description of the invention
Hereinafter the detailed description of the invention of the present invention is described in detail.It should be appreciated that this place
The detailed description of the invention described is merely to illustrate and explains the present invention, is not limited to the present invention.
The preparation method of the pyridine side chain methyl quaternary ammonium salt compounds that the present invention provides, described pyridine side
Chain methyl quaternary ammonium salt compounds is the compound of structure shown in formula (1), wherein, the method include as
Lower step:
(1) in the presence of bisulfites and catalyst, by compound and the bromine of structure shown in formula (4)
The aqueous solution of hydrochlorate carries out after two-phase bromination reaction obtains the compound of structure shown in formula (3), isolating
Organic phase；
(2) compound of the organic phase obtained in step (1) with structure shown in formula (2) is connect
Touch reaction, obtain the compound of structure shown in formula (1)；
Wherein, in formula (1), formula (2), formula (3) and formula (4), R1And R2The most independent
Ground is selected from C1-C8Alkyl, R3、R4And R5It is each independently selected from C1-C4Alkyl.
In the present invention, the alkyl of described C1-C8 can be straight chain, it is also possible to be side chain.Institute
The example of the alkyl stating C1-C8 can include but not limited to: methyl, ethyl, n-pro-pyl, isopropyl
Base, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl, new penta
Base, n-hexyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 1,1,2-thmethylpropyl, 1,2,2-thmethylpropyl, 1-ethyl-butyl, 2-
Ethyl-butyl, 1-Ethyl-2-Methyl propyl group, n-heptyl and n-octyl.In these groups, it is preferably
Methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl and octyl group.
In the present invention, the alkyl of described C1-C4 can be straight chain, it is also possible to be side chain.Institute
The example of the alkyl stating C1-C4 may include that methyl, ethyl, n-pro-pyl, isopropyl, positive fourth
Base, sec-butyl, isobutyl group and the tert-butyl group.In these groups, preferably methyl, ethyl, propyl group and
Butyl.
In the case of and specifically, it is preferable to, R1And R2Be each independently selected from methyl, ethyl, propyl group,
Butyl, amyl group, hexyl, heptyl and octyl group, R3、R4And R5It is each independently selected from methyl, second
Base, propyl group and butyl.
It is highly preferred that R1And R2It is each independently selected from methyl, ethyl, propyl group and butyl, described formula
(2) compound of structure shown in is triethylamine or tripropyl amine (TPA).
In the present invention, can pass through commercially available as the compound of structure shown in the formula (4) of raw material,
Can also pass through disclosed in patent US4723011, EP0965589, US5227491, US5371229
Synthetic method prepares.
Preferably, shown in described formula (4), the compound of structure is 5-methyl-2,3-pyridinedicarboxylic acid methyl esters,
5-methyl-2,3-pyridinedicarboxylic acid ethyl ester, 5-methyl-2,3-pyridinedicarboxylic acid propyl ester or 5-methyl-2,3-pyridine
The dicarboxylic acids tert-butyl ester.
According to the present invention, in order to increase the contact area of two phase reaction, in step (1), described formula (4)
The compound of shown structure uses in the way of dissolving in organic solvent；Preferably, relative to 1 mole
Described formula (4) shown in the compound of structure, the consumption of described organic solvent is 3-8 mole, more excellent
Elect 4-7 mole as.
According to the present invention, described organic solvent can be organic solvent commonly used in the art, specifically, institute
Stating organic solvent, to be selected from esters solvent, alkane solvents, aromatic hydrocarbon solvent or halogenated hydrocarbon molten
Agent, wherein, described esters solvent is C2-C10Ester, described alkane solvents is C1-C10Alkane,
Described aromatic hydrocarbon solvent is C6-C12Aromatic hydrocarbon, described halogenated hydrocarbon solvent is C1-C10Alkane or
C6-C12The halides (preferably chloro thing or bromo-derivative) of aromatic hydrocarbon.It is highly preferred that it is described organic
Solvent can be ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, n-hexane, hexamethylene
In alkane, benzene, chlorobenzene, dichloro-benzenes, dichloromethane, chloroform, carbon tetrachloride and dichloroethanes
One or more.
In accordance with the present invention it is preferred that, described bisulfites uses in the way of being dissolved in water, institute
The concentration stating bisulfites can be 0.2-1.2g/mL, preferably 0.5-0.7g/mL.
In the present invention, described bisulfites is preferably sodium hydrogensulfite and/or potassium bisulfite.
According to the present invention, the concentration of the bromate in the aqueous solution of described bromate can be
0.1-1g/mL, preferably 0.15-0.5g/mL.
Preferably, described two-phase bromination reaction is, in the presence of bisulfites and catalyst, by institute
That states that the aqueous solution of bromate is added drop-wise to containing the compound of structure shown in described formula (4) is described organic molten
In agent.
Aqueous solution rate of addition as described bromate can change in wide scope.Preferably,
The compound of structure, the water of the described bromate in terms of bromate shown in formula (4) relative to 1 mole
The rate of addition of solution is 0.025-0.35 mol/hr, preferably 0.1-0.2 mol/hr.
According to the present invention, described bromate is preferably sodium bromate and/or potassium bromate, more preferably bromic acid
Sodium.
In the case of according to the invention it is preferred to, organic phase and the formula (2) that will obtain in described step (1)
Before the compound of shown structure carries out haptoreaction, the organic phase obtained in described step (1) is entered
Row is cleaned and is dried.Described cleaning can use this area conventional method with drying means, reaches to purify institute
State the purpose of organic phase.Such as, the water washing organic phase of available 1-5 times of volume is once above (excellent
Elect as 1-3 time), then collect organic phase, add anhydrous sodium sulfate and be dried, filter.
According to the present invention, described catalyst is that this area carries out the conventional use of catalyst of bromo-reaction.
Described catalyst is preferably cyclohexanone peroxide, dibenzoyl peroxide, TBHP, idol
One or more in nitrogen bis-isobutyronitrile and ABVN, more preferably azodiisobutyronitrile.
According to the present invention, generally, to the compound of structure shown in described formula (4) and described bromine
The consumption of hydrochlorate and described bisulfites has no particular limits, and meets and will tie described formula (4) Suo Shi
The compound of structure can carry out bromo-reaction well.In the present invention, it is preferred to described formula (4)
Shown in compound and the described bromate of structure and the mol ratio of described bisulfites be preferably 1:
0.5-1:0.5-1, more preferably 1:0.55-0.7:0.55-0.8.
According to the present invention, the consumption of described catalyst can change in the larger context.Preferable case
Under, described in step (1), shown in formula (4), the compound of structure is permissible with the mol ratio of described catalyst
For 1:0.001-0.05, preferably 1:0.008-0.01.
According to the present invention, described two-phase bromination reaction condition meets described two-phase bromo-reaction and carries out i.e.
Can, described reaction temperature is preferably more than 50 DEG C, more preferably 50-80 DEG C, and the reaction time is 0.5-20
Hour.
According to the invention it is preferred to the two-phase bromination reaction of the present invention is back flow reaction, i.e. at condensing unit
, when heating reactant, there is steam in middle reaction, and steam constantly returns anti-at condensation in-tube condensation
Answering in device, thus prevent reactant in reactor from escaping, wherein, condensing unit is conventional in this area
Device.This is well known to those skilled in the art, and is not described here in detail.
According to the present invention, in step (2), by then passing through the organic phase that will obtain in step (1)
Carry out haptoreaction with the compound of structure shown in formula (2), obtain the chemical combination of structure shown in formula (1)
Thing, and carry out bromination by the method for step of the present invention (1), it is possible to obtain high bromination rate.
Therefore, in the present invention, shown in described formula (2), the consumption of the compound of structure can be according to described formula
(4) consumption of the compound of structure shown in determines, it is preferable that the change of structure shown in described formula (2)
Compound is 1:0.4-0.8 with the mol ratio of the compound of structure shown in described formula (4), more preferably 1:
0.5-0.7。
According to the present invention, in step (2), the most described catalytic condition includes: reaction temperature
For 0-40 DEG C, the reaction time is 1-3 hour.
According to the present invention, for the change of structure shown in the organic phase that will obtain in step (1) and formula (2)
Compound carries out the mode that contacts, and there is no particular limitation, as long as this feed postition makes the temperature of reaction system
Less than 40 DEG C.This feed postition can be straight for the compound of structure shown in the most described formula (2)
Connect and add in the organic phase obtained in described step (1), it is also possible to for tying described formula (2) Suo Shi
The dropping of the compound of structure is added in described step (1) in the organic phase obtained.In them, preferably will
In the organic phase being added drop-wise in described step (1) obtain of the compound of structure shown in described formula (2).
As the rate of addition of the compound of structure shown in described formula (2), there is no particular limitation, as long as controlling
Haptoreaction system temperature is less than 40 DEG C.
Hereinafter will be described the present invention by embodiment.In following example, the product obtained
Purity use HPLC method (manufacturer: Agilent company, model: Agilent 1260) record.
In following example, the yield of the product obtained calculates in the following way:
Mole × 100% of the compound of structure shown in the mole/formula (4) of yield=obtain product；
In following example, 5-methyl-2,3-pyridinedicarboxylic acid ethyl ester is by implementing in patent EP0965589
Prepared by the method for example 5,5-methyl-2, and 3-pyridinedicarboxylic acid methyl esters is by embodiment in patent EP0965589
Prepared by the method for 12.
Embodiment 1
The present embodiment is used for [(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester is described
Preparation method.
5-methyl-2,3-pyridinedicarboxylic acid ethyl ester 120.0g, Asia it is sequentially added in 1000mL round-bottomed flask
Niter cake 32.0g, azodiisobutyronitrile 0.7g, ethyl acetate 300mL, water 50mL, heat temperature raising
To 60 DEG C, in reaction system, drip the 300mL aqueous solution of 50g sodium bromate, control reaction temperature and exist
60 DEG C, 6h dropping is complete, 70 DEG C of insulation reaction 2h, and reaction terminates, layering, organic phase 400mL
Water washing, in triplicate, collect organic phase, add anhydrous sodium sulfate and be dried, filter, filtrate proceeds to
Another 1000mL round-bottomed flask, under room temperature, drips 31.2g triethylamine to reaction system, within 1 hour, adds
Finishing, be stirred at room temperature 3 hours, filter, filter cake is white particulate crystal, dries [(5,6-dicarboxyl-3-
Pyridine radicals)-methyl] triethylamine ammonium bromide diethylester 125.4g, yield is 59.1%, and purity is 98 weights
Amount %.
Embodiment 2
The present embodiment is used for [(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide dimethyl ester is described
Preparation method.
5-methyl-2,3-pyridinedicarboxylic acid methyl esters 210.0g, Asia it is sequentially added in 1000mL round-bottomed flask
Niter cake 64.1g, azodiisobutyronitrile 1.5g, ethyl acetate 400mL, water 150mL, heating rises
Temperature, to 45 DEG C, drips the 200mL aqueous solution of 99.9g sodium bromate in reaction system, controls reaction temperature
Degree is at 65-70 DEG C, and 4h dropping is complete, 50 DEG C of insulation reaction 3h, after reaction terminates, and layering, organic phase
Successively with the water washing of 600mL, in triplicate, collect organic phase, add anhydrous sodium sulfate and be dried, mistake
Filter, filtrate proceeds to another 1000mL round-bottomed flask, under room temperature, drips 55.5g tri-second to reaction system
Amine, finishes for 1 hour, is stirred at room temperature 3 hours, filters, and filter cake is white particulate crystal, dries
[(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide dimethyl ester 201.9g, yield is 51%, pure
Degree is 98 weight %.
Embodiment 3
The present embodiment is used for [(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester is described
Preparation method.
5-methyl-2,3-pyridinedicarboxylic acid ethyl ester 120.0g, Asia it is sequentially added in 1000mL round-bottomed flask
Niter cake 30.3g, azodiisobutyronitrile 0.7g, ethyl acetate 300mL, water 50mL, heat temperature raising
To 55 DEG C, in reaction system, drip the 100mL aqueous solution of 46.1g sodium bromate, control reaction temperature
At 55-60 DEG C, 4h dropping is complete, 70 DEG C of insulation reaction 3h, and reaction terminates, layering, and organic phase is used
The water washing of 400mL, in triplicate, collects organic phase, adds anhydrous sodium sulfate and be dried, filter, filter
Liquid proceeds to another 1000mL round-bottomed flask, under room temperature, to reaction system drip 31.2g triethylamine, 1
Hour finishing, be stirred at room temperature 3 hours, filter, filter cake is white particulate crystal, dries [(5,6-bis-
Carboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester 97.4g, yield is 45.8%, and purity is 98
Weight %.
Embodiment 4
The present embodiment is used for [(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester is described
Preparation method.
5-methyl-2,3-pyridinedicarboxylic acid ethyl ester 120.0g, Asia it is sequentially added in 1000mL round-bottomed flask
Niter cake 52.0g, azodiisobutyronitrile 0.7g, ethyl acetate 300mL, water 50mL, heat temperature raising
To 70 DEG C, in reaction system, drip the 100mL aqueous solution of 75.4g sodium bromate, control reaction temperature
At 70 DEG C, 3h dropping is complete, 70 DEG C of insulation reaction 3h, and reaction terminates, layering, and organic phase is used
The water washing of 400mL, in triplicate, collects organic phase, adds anhydrous sodium sulfate and be dried, filter, filter
Liquid proceeds to another 1000mL round-bottomed flask, under room temperature, to reaction system drip 31.2g triethylamine, 1
Hour finishing, be stirred at room temperature 3 hours, filter, filter cake is white particulate crystal, dries [(5,6-bis-
Carboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester 78.9g, yield is 37.1%, and purity is 97
Weight %.
Embodiment 5
The present embodiment is used for [(5,6-dicarboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester is described
Preparation method.
5-methyl-2,3-pyridinedicarboxylic acid ethyl ester 145.2g, Asia it is sequentially added in 1000mL round-bottomed flask
Niter cake 57.6g, azodiisobutyronitrile 1.2g, ethyl acetate 300mL, water 50mL, heat temperature raising
To 50 DEG C, in reaction system, drip the 250mL aqueous solution of 92.4g sodium bromate, control reaction temperature
At 50 DEG C, 4h dropping is complete, 50 DEG C of insulation reaction 6h, and reaction terminates, layering, and organic phase is used
The water washing of 400mL, in triplicate, collects organic phase, adds anhydrous sodium sulfate and be dried, filter, filter
Liquid proceeds to another 1000mL round-bottomed flask, under room temperature, to reaction system drip 29.2g triethylamine, 1
Hour finishing, be stirred at room temperature 3 hours, filter, filter cake is white particulate crystal, dries [(5,6-bis-
Carboxyl-3-pyridine radicals)-methyl] triethylamine ammonium bromide diethylester 81.5g, yield is 32.2%, content 98 weight
Amount %.
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to above-mentioned
Detail in embodiment, in the technology concept of the present invention, can be to the skill of the present invention
Art scheme carries out multiple simple variant, and these simple variant belong to protection scope of the present invention.
It is further to note that each the concrete technology described in above-mentioned detailed description of the invention is special
Levy, in the case of reconcilable, can be combined by any suitable means, in order to avoid not
Necessary repetition, various possible combinations are illustrated by the present invention the most separately.
Additionally, can also be combined between the various different embodiment of the present invention, as long as
It is without prejudice to the thought of the present invention, and it should be considered as content disclosed in this invention equally.
Claims (11)
1. a preparation method for pyridine side chain methyl quaternary ammonium salt compounds, described pyridine side chain methyl
Quaternary ammonium compound is the compound of structure shown in formula (1), it is characterised in that the method include as
Lower step:
(1) in the presence of bisulfites and catalyst, by compound and the bromine of structure shown in formula (4)
The aqueous solution of hydrochlorate carries out after two-phase bromination reaction obtains the compound of structure shown in formula (3), isolating
Organic phase；
(2) compound of the organic phase obtained in step (1) with structure shown in formula (2) is connect
Touch reaction, obtain the compound of structure shown in formula (1)；
Wherein, in formula (1), formula (2), formula (3) and formula (4), R1And R2The most independent
Ground is selected from C1-C8Alkyl, R3、R4And R5It is each independently selected from C1-C4Alkyl；
Preferably, R1And R2It is each independently selected from C1-C4Alkyl, structure shown in described formula (2)
Compound be triethylamine or tripropyl amine (TPA).
Preparation method the most according to claim 1, wherein, in step (1), described formula (4)
The compound of shown structure uses in the way of dissolving in organic solvent；
Preferably, shown in the described formula (4) relative to 1 mole, the compound of structure, described organic molten
The consumption of agent is 3-8 mole；
It is highly preferred that described organic solvent is selected from esters solvent, alkane solvents, aromatic hydrocarbon solvent
Or halogenated hydrocarbon solvent, wherein, described esters solvent is C2-C10Ester, described alkane solvents is
C1-C10Alkane, described aromatic hydrocarbon solvent is C6-C12Aromatic hydrocarbon, described halogenated hydrocarbon solvent is
C1-C10Alkane or C6-C12The halides of aromatic hydrocarbon.
Preparation method the most according to claim 1 and 2, wherein, described catalyst is peroxidating
Cyclohexanone, dibenzoyl peroxide, TBHP, azodiisobutyronitrile and azo two different heptan
One or more in nitrile, preferably azodiisobutyronitrile.
Preparation method the most according to claim 1 and 2, wherein, described bisulfites is with molten
Mode in Xie Shui uses, and the concentration of described bisulfites is 0.2-1.2g/mL；
Preferably, described bisulfites is sodium hydrogensulfite and/or potassium bisulfite.
5. according to the preparation method described in any one in claim 1-4, wherein, described bromate
The aqueous solution in the concentration of bromate be 0.1-1g/mL；
Preferably, described two-phase bromination reaction is, in the presence of bisulfites and catalyst, by institute
That states that the aqueous solution of bromate is added drop-wise to containing the compound of structure shown in described formula (4) is described organic molten
In agent；
It is highly preferred that the compound of structure shown in formula (4) relative to 1 mole, in terms of bromate
The rate of addition of the aqueous solution of described bromate is 0.025-0.35 mol/hr.
Preparation method the most according to claim 1, wherein, described bromate be sodium bromate and/or
Potassium bromate, preferably sodium bromate.
Preparation method the most according to claim 1 and 2, wherein, by obtain in step (1)
Before shown in organic phase and formula (2), the compound of structure carries out haptoreaction, by described step (1)
The organic phase obtained carries out cleaning and being dried.
8. according to the preparation method described in any one in claim 1-6, wherein, in step (1),
Shown in described formula (4), the compound of structure with the mol ratio of described bromate and described bisulfites is
1:0.5-1:0.5-1, preferably 1:0.55-0.7:0.55-0.8.
9. according to the preparation method described in any one in claim 1-7, wherein, in step (1),
The compound of structure shown in described formula (4) and the mol ratio of described catalyst are 1:0.001-0.05.
10. according to the preparation method described in any one in claim 1-8, wherein, described two-phase bromine
Changing reaction condition is: reaction temperature is 50-80 DEG C, and the reaction time is 0.5-20 hour.
11. preparation methods according to claim 1, wherein, structure shown in described formula (4)
Compound is 1:0.5-0.8 with the mol ratio of the compound of structure shown in described formula (2)；
Preferably, described haptoreaction is for being added drop-wise to institute by the compound of structure shown in described formula (2)
State in the organic phase obtained in step (1)；
It is highly preferred that described catalytic condition includes: reaction temperature is 0-40 DEG C, the reaction time
For 1-3 hour.
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| CN107216286A (en) * | 2017-06-27 | 2017-09-29 | 江苏省农用激素工程技术研究中心有限公司 | The preparation method of the pyridinedicarboxylic acid dimethyl ester of 5 bromomethyl 2,3 |
| CN108727254A (en) * | 2017-04-21 | 2018-11-02 | 山东方明邦嘉制药有限公司 | A kind of synthetic method of 4- picolines quaternary ammonium salt |
| CN110234628A (en) * | 2016-11-21 | 2019-09-13 | 阿达玛阿甘有限公司 | The method for preparing methoxypicoline dicarboxylic acid esters |
| CN110818627A (en) * | 2018-08-09 | 2020-02-21 | 北京颖泰嘉和生物科技股份有限公司 | Preparation method of 5-methoxymethyl-2, 3-pyridinedicarboxylic acid diester |
| CN113004197A (en) * | 2019-12-19 | 2021-06-22 | 北京颖泰嘉和生物科技股份有限公司 | Method for recovering 5-methyl-2, 3-pyridinedicarboxylic acid diester |
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| CN114904474A (en) * | 2022-05-26 | 2022-08-16 | 内蒙古新农基科技有限公司 | 5-bromomethylpyridine-2, 3-dicarboxylic acid diethyl ester reaction device and method |
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