CN108383718A - The preparation method of one kind 2,4,5- trifluoro benzene acetic acids - Google Patents
The preparation method of one kind 2,4,5- trifluoro benzene acetic acids Download PDFInfo
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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Abstract
The present invention relates to a kind of preparation methods of 2,4,5 trifluoro benzene acetic acids, belong to pharmaceutical intermediate synthesis technical field.In order to solve the problems, such as that existing raw material is dangerous high, one kind 2 is provided, 4, the preparation method of 5 trifluoro benzene acetic acids, this method is included under strong acid effect, reacts 2 methyl, 4 nitrobenzoic acid to form diazonium salt dissolving with nitrite, adds hydrofluoric acid or borofluoride is fluorinated, pyrolysis, obtains II compound of formula；In the presence of acid binding agent, II compound of formula carries out acylation reaction with haloacetyl chloride, obtains III compound of formula；Under alkali metal alcohol salt action, III compound of formula is reacted with alcohol, obtains IV compound of formula；IV compound of formula is hydrolyzed under acid system and is handled with decarboxylation, using diazotising is carried out after reduction again, is pyrolyzed, obtains 2,4,5 trifluoro benzene acetic acids.The present invention improves the conversion ratio of raw material, ensures the quality requirement of product yield and purity, realizes the effect of the high total recovery of final product.
Description
Technical field
The present invention relates to a kind of preparation methods of 2,4,5- trifluoro benzene acetic acids, belong to pharmaceutical intermediate synthesis technical field.
Background technology
Sitagliptin is for treating the dipeptidyl peptidase IV of type II diabetes (DDP-4) inhibitor class drug, is a kind of
Novel antidiabetic drug, the drug account for global diabetes drug medication share and reach 20% or more, and market demand is equivalent to.And 2,4,5-
Key intermediate of the trifluoroacetic acid as synthesis sitagliptin, has extensive market prospects.
Route is mainly the following for the synthesis of 2,4,5- trifluoroacetic acids in existing literature.As Chinese patent (authorizes
Notification number：CN104387259B after one kind disclosed in) is first converted into grignard reagent with trifluorobromobenzene, then in the presence of TMEDA with
Diethy-aceto oxalate is reacted through addition reaction, then with hydrazine hydrate/potassium hydroxide/diethylene glycol, and corresponding 2,4 are obtained after acidified,
5- trifluoroacetic acids.
Although the synthetic route of this method is relatively short, the cost of material selected in the synthesis that this method respectively walks is expensive
Such as hydrazine hydrate, diethy-aceto oxalate, more mainly this method need to synthesize that grignard reagent stability is poor, and the safety of grignard reagent
Also poor, it is unfavorable for industrializing, and the yield of the reaction is relatively relatively low.
For another example Chinese patent application (publication number：CN1749232A) disclose it is a kind of trifluoro-benzene is subjected to chloromethylation, then
Carry out it is cyanalation, finally hydrolysis obtain corresponding 2,4,5- trifluoro benzene acetic acids.
Equally, although this method route is shorter, the reaction corrosivity of its chloromethylation is big, and more importantly due to
Its Cymag used or potassium cyanide belong to hypertoxicity substance, dangerous big, are unfavorable for actual production operation.
Also have in order to solve the problems, such as some present in above-mentioned synthesis route, in existing literature and proposes new synthesis side
Method is to solve the above problems, such as Chinese patent application (publication number：CN107522609A it) discloses a kind of former for starting with aniline
Material, is added sodium nitrite, then sodium fluoborate reactant aqueous solution is added dropwise and obtains 2,3,5- trifluoromethyl anilines in glacial acetic acid；Again in ice second
2,3,5- trifluoromethyl anilines and butter of tin-polystyrene complex, then liquid feeding bromine are added in acid, after post-processing, obtains 2,3,5-
Three fluoro- 6- bromanilines, add NaH and ethyl acetate, are reacted under the high temperature conditions under the action of copper bromide, acidification, then add
Sodium nitrite diazotising obtains corresponding product 2,3,5- trifluoro benzene acetic acids.
Although solving the above problem to a certain extent ,-the NH in the starting material used2In reaction process
In the raw material bromine and NaH that are easily converted into the by-product of-F, and are used in reaction process be equally dangerous substances, safety compared with
Difference.
Invention content
The present invention is directed to the above defect existing in the prior art, provides a kind of preparation side of 2,4,5- trifluoro benzene acetic acids
Method solves the problems, such as it is how to realize to reduce cost and improve safety and have both the requirement of high-purity quality.
The purpose of the present invention is what is be achieved by the following technical programs, the preparation side of one kind 2,4,5- trifluoro benzene acetic acids
Method, which is characterized in that this approach includes the following steps：
A, under strong acid effect, 2- methyl -4- nitrobenzoic acids are reacted with nitrite after forming diazonium salt dissolving, then plus
Enter hydrofluoric acid or borofluoride carries out fluorination reaction, pyrolysis obtains II compound of formula；
B, in the presence of acid binding agent, II compound of formula and haloacetyl chloride is subjected to acylation reaction, obtain III chemical combination of formula
Object；
C, under the action of alkali metal alcoholates, III compound of formula is reacted with ROH alcoholic solvents, obtains IV compound of formula；
D, IV compound of formula is hydrolyzed under acid system and is handled with decarboxylation, obtain V compound of formula；Again by formula V
Nitro in compound carries out diazo-reaction again after reduction, and pyrolysis obtains 2,4,5- trifluoro benzene acetic acid of type I compound；
By using 2- methyl -4- nitrobenzoic acids as raw material, reacting to form diazonium with nitrite by acting in strong acid
The form of salt makes the C of the unsubstituted position in the phenyl ring of 2- methyl -4- nitrobenzoic acids form C+Form, realize effective benzene
The purpose of fluorine is introduced on ring；Meanwhile nitro can be effectively avoided to be converted to F bases in fluorination reaction process using nitro compound
Group realizes the effect for effectively reducing by-product, improves the intermediate yield and purification effect generated.In addition, due to the introducing of nitro,
The activity that can influence the activity and raising methyl of F groups and-COOH group on phenyl ring, makes in acylation process effectively in first
The effect that haloacetyl is introduced on base, can also avoid the production of other by-products, to make first two steps high conversion and subtract
The generation of few side reaction, improves the yield and purity Coriolis mass of the intermediate of each step, using subsequent esterification, hydrolysis and decarboxylation,
Reduction and diazotising, finally obtain corresponding product.Simultaneously as it is original that the present invention, which has selected 2- methyl -4- nitrobenzoic acids,
Material, has selected rational synthetic route, and the raw material during each step can be made to react all has safe and lower-cost excellent
Point, and the condition in each step reaction process is relatively mild, substantially without carrying out under the high temperature conditions, without using Cymag
Or dangerous higher and price the raw material such as bromine, the advantages of advantageously reducing cost and realize industrialized production, the present invention
Reaction in each raw material dosage according to the general molar equivalent ratio of chemical field can or by catalytic amount be added.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, strong acid is selected from described in step A
Concentrated hydrochloric acid, the concentrated sulfuric acid, formic acid or acetic acid；The nitrite is sodium nitrite or potassium nitrite.It can make to effectively form weight
Nitridation salt preferably activates the activity of the C of unsubstituted position on the phenyl ring of 2- methyl -4- nitrobenzoic acids, and making subsequently can be more preferable
On three corresponding positions introduce F groups；Meanwhile also have the advantages that raw material be easy to get with it is at low cost, be conducive to preferably reach
To the purpose for reducing cost.Here the dosage of strong acid and nitrite is according to the common usage ratio of the field of chemical synthesis.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, borofluoride described in step A
For fluorine boron salt acid sodium；Temperature≤10 DEG C of the fluorination reaction.So that reaction is carried out under conditions of milder, is also beneficial to
The generation for reducing by-product is conducive to improve yield and purity Coriolis mass requirement.Scheme as a further preference, the fluorination are anti-
The temperature answered is -5 DEG C~5 DEG C.Raw material is selected according to general molar equivalent for the dosage of borofluoride or hydrofluoric acid,
It is 1 preferably to make the molar ratio of 2- methyl -4- nitrobenzoic acids therein and borofluoride or hydrofluoric acid：1.5~1：3.60.Purpose
It is waste in order to reduce raw material and avoids reacting not exclusively the requirements such as the purity Coriolis mass for influencing product.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, the choosing of acid binding agent described in step B
From one or more of triethylamine, diisopropylethylamine, diethanol amine and pyridine.It can make and be formed in reaction process
HCl reacts and achievees the purpose that remove the small molecule acid in reaction system, to enable reaction preferably to be carried out to positive reaction,
Improve the transformation efficiency and yield effect of reaction；Meanwhile these raw materials also have the advantages that cost price is relatively low.Certainly, here
The acid binding agent is preferably with triethylamine.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, haloacetyl described in step B
Chlorine is selected from dichloroacetyl chloride or trichloro-acetic chloride；The temperature of acylation reaction described in step B is 20 DEG C~35 DEG C.Substantially in room temperature
Under the conditions of reaction can be made effectively to carry out, have reaction mild, easily operated advantage.Further preferred embodiment, most
It is to be reacted under 25 DEG C~30 DEG C of temperature condition well.Preferably make 2- methyl -4- nitrobenzoic acids therein and halogenated second
The molar ratio of acyl chlorides is 1：1~1：1.30.Purpose is waste in order to reduce raw material and avoids reacting and not exclusively influence product
The requirements such as purity Coriolis mass.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, for the acylation reaction process of step B, generally having
It is carried out in solvent, but the quality of product and yield effect in order to better improve, preferably, institute in step B
It states acylation reaction to carry out in water-insoluble solvent, the ice water that is added after reaction is post-processed, described water-insoluble
Solvent is selected from dichloromethane or ethyl acetate.It can make material dissolution in water-insoluble solvent, two are formed after adding ice water
After phase system, achieve the purpose that be separated by filtration since the addition of ice water can be such that material is more effectively precipitated, meanwhile, pass through addition
Ice water can make remaining a small amount of haloacetyl chloride hydrolysis in reaction process and have the function that remove, and avoid one under the influence of it
The reaction of step advantageously reduces the formation of by-product, improves yield and the purity Coriolis mass requirement of generation.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, alkali metal alcohol described in step C
Salt is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide；The ROH alcoholic solvents are selected from methanol, second
One or more of alcohol and propyl alcohol.Most raw material is easy to get and advantage at low cost.Generally for the dosage of alkali metal alcoholates
It preferably adds according to catalytic amount, further says, keep the alkali metal alcoholates of selection corresponding with ROH alcoholic solvents.Even adopt
With sodium ethoxide, then solvent is made to use ethyl alcohol；According to sodium methoxide, then make solvent using methanol etc. in correspondence.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, described in step D restore specific
For：
The nitro in V compound of formula is subjected to catalysis reduction under the action of palladium-containing catalyst or persulfide reducing agent
Obtain corresponding VI compound of midbody product formula；
Nitro can be made to be converted to amino well, and on have the advantages that transformation efficiency is high.Side as a further preference
Case, the palladium-containing catalyst are palladium carbon；The persulfide reducing agent is selected from sodium persulfide or over cure potassium.It is restored with catalysis
The high advantage of performance；Certainly, preferably make to be restored using persulfide here, can make reaction in aqueous solution can be real
Existing, having the advantages that have relative to palladium carbon preferably reduces cost.The dosage of palladium carbon or persulfide is catalyzed according to it
Amount is added.
In the preparation method of above-mentioned 2,4,5- trifluoro benzene acetic acids, preferably, diazotising is anti-described in step D
Should be specially：
VI compound of formula carries out diazo-reaction with sodium nitrite under≤10 DEG C of temperature condition in glacial acetic acid.This
In mainly for more effectively enabling amino therein more effectively react to form diazonium compound with nitrite, then pass through heat
Achieve the purpose that remove amino after solution.
Following reactional equation may be used in the specific reaction route of the preparation method of 2,4, the 5- trifluoro benzene acetic acids of the present invention
Formula indicates：
In conclusion compared with prior art, the present invention haing the following advantages：
1. by using new starting material 2- methyl -4- nitrobenzoic acids, it can successfully avoid on phenyl ring nitro position by F
Substitution and raising methyl activity, to realize that introducing haloacetyl effectively on methyl makes subsequently to effectively form acetate
Group, and the characteristic since nitro is effectively utilized allow to the generation for reducing by-product in reaction process, improve raw material
Conversion ratio realizes the quality requirement for ensureing product yield and purity, the yield of every step is made to have reached higher level, to
It can realize that final product total recovery also handles higher level.
2. the reaction route of the present invention is while it seem that route is longer, but as a result of 2- methyl -4- nitrobenzoyls
Acid is used as starting material, keeps each step more suitable to the selection of raw material and auxiliary material, the advantage of lower cost of each raw material allows to more preferably
Reduction production cost, and the safety of selected raw material is higher；And also have the advantages that by-product is few, be conducive to more preferable
Raising yield and purity effect, resultant effect have better advantage.
Specific implementation mode
Below by specific embodiment, the technical solutions of the present invention will be further described, but the present invention is simultaneously
It is not limited to these embodiments.
Embodiment 1
Then it is slow cooling to 5 DEG C in reactor input 2- methyl -4- nitrobenzoic acids 36.5g and glacial acetic acid 200mL
Put into sodium nitrite 17g again below, after, then etching acid 14g is added dropwise, after being added dropwise, control temperature is carried out at 5 DEG C or less
Fluorination reaction after middle control confirms that raw material has reacted, then heats up and carries out pyrolysis 30min at 20 DEG C~25 DEG C, adds dichloromethane
150mL and water 50mL, after stirring 30min, stands, layering, and the dichloromethane solution for obtaining II compound containing formula is directly used in down
The reaction of one step, single step yield reach 95.8%；
The dichloromethane solution of above-mentioned II compound containing formula is put into another reaction bulb, then puts into pyridine 16g, control temperature
Degree at ambient temperature, is added dropwise trichloro-acetic chloride 36g, makes that the reaction was complete after completion of dropwise addition, then by material be transferred in ice water into
Row ice solution makes precipitation material, filters, obtains III compound of midbody product formula, single step yield reaches 96.7%；
Obtained III compound of formula is put into reaction bulb again, ethyl alcohol 200mL is added, adds sodium ethoxide 2g, is controlled
Temperature is reacted at ambient temperature to be made after the reaction was complete, to obtain IV compound of intermediate product formula, then put into 200g concentrated hydrochloric acids, is risen
Temperature is hydrolyzed to reflux and decarboxylic reaction, after reaction, 100mL dichloromethane is added and carries material, stand, layering, collect two
Chloromethanes phase is concentrated to give intermediate product, then by the intermediate product plus in 200g water, 15g sodium carbonate, 10g over cures is added
Sodium is reacted under room temperature to complete, after reaction, is added 100mL dichloromethane and is carried material, concentration removes solvent extremely
It is dry, it obtains corresponding intermediate material and is added in another reaction bulb, add glacial acetic acid 200mL, control temperature is at 5 DEG C or less
Put into sodium nitrite 17g and carry out diazo-reaction to complete, then, be warming up to 25 DEG C be pyrolyzed after, add water and acetic acid
Ethyl ester is extracted, and is stood, is layered, and ethyl acetate phase is collected, and is removed solvent, is obtained 2,4,5- trifluoro benzene acetic acid of target product
27g, yield 71%, purity reaches 98.6%.
Embodiment 2
Reactor put into 2- methyl -4- nitrobenzoic acids 36.5g and formic acid 200mL, then, be slow cooling to 5 DEG C with
Under put into sodium nitrite 20.7g again, after, then sodium fluoborate 80g is added dropwise, after being added dropwise, control temperature 5 DEG C or less after
It is continuous to carry out fluorination reaction, it after middle control confirms that raw material has reacted, then heats up and carries out pyrolysis 30min at 20 DEG C~25 DEG C, add two
Chloromethanes 150mL and water 50mL, after stirring 30min, stands, layering, and the dichloromethane solution for obtaining II compound containing formula is direct
For the reaction of next step, single step yield reaches 94.6%；
The dichloromethane solution of above-mentioned II compound containing formula is put into another reaction bulb, then puts into pyridine 18g, control temperature
Degree at ambient temperature, is added dropwise trichloro-acetic chloride 40g, makes that the reaction was complete after completion of dropwise addition, then by material be transferred in ice water into
Row ice solution makes precipitation material, filters, obtains III compound of midbody product formula, single step yield reaches 93.6%；
Obtained III compound of formula is put into reaction bulb again, ethyl alcohol 200mL is added, adds sodium methoxide 1.6g, is controlled
Temperature processed is reacted at ambient temperature to be made after the reaction was complete, to obtain IV compound of intermediate product formula, then put into 200g concentrated hydrochloric acids,
It is warming up to reflux to be hydrolyzed and decarboxylic reaction, after reaction, 100mL dichloromethane is added and carries material, stand, layering, collection
Dichloromethane phase is concentrated to give intermediate product, then by the intermediate product plus in 200g water, 15g sodium carbonate, 12g over cures is added
Change sodium, reacted under room temperature to complete, after reaction, adds 100mL dichloromethane and carry material, concentration removing solvent
It to doing, obtains corresponding intermediate material and is added in another reaction bulb, add formic acid 150mL, control temperature is at 5 DEG C or less
Put into sodium nitrite 20g and carry out diazo-reaction to complete, then, be warming up to 25 DEG C be pyrolyzed after, add water and acetic acid
Ethyl ester is extracted, and is stood, is layered, and ethyl acetate phase is collected, and is removed solvent, is obtained 2,4,5- trifluoro benzene acetic acid of target product
28g, yield 73%, purity reaches 98.8%.
Embodiment 3
Reactor put into 2- methyl -4- nitrobenzoic acids 36.5g and formic acid 200mL, then, be slow cooling to 10 DEG C with
Under put into sodium nitrite 29.5g again, after, then sodium fluoborate 82g is added dropwise, after being added dropwise, control temperature is at 5 DEG C~10 DEG C
Continue fluorination reaction, after middle control confirms that raw material has reacted, then heats up and carry out pyrolysis 30min at 20 DEG C~25 DEG C, add
Ethyl acetate 200mL and water 50mL, after stirring 30min, stands, layering, and the ethyl acetate solution for obtaining II compound containing formula is straight
The reaction for next step is connect, single step yield reaches 94.8%；
The ethyl acetate solution of above-mentioned II compound containing formula is put into another reaction bulb, then puts into diisopropylethylamine
30g, control temperature are added dropwise trichloro-acetic chloride 42g, make that the reaction was complete after completion of dropwise addition under conditions of 20~25 DEG C, then by object
Material, which is transferred to progress ice solution in ice water, makes precipitation material, filters, obtains III compound of midbody product formula, single step yield reaches
94.2%；
Obtained III compound of formula is put into reaction bulb again, propyl alcohol 200mL is added, adds sodium tert-butoxide 3.0g,
Control temperature is reacted at ambient temperature to be made after the reaction was complete, to obtain IV compound of intermediate product formula, then put into 200g concentrated hydrochloric acids
In, it is warming up to reflux and is hydrolyzed and decarboxylic reaction, after reaction, 100mL ethyl acetate is added and carries material, stand, layering, receipts
Collect ethyl acetate phase, is concentrated to give intermediate product, then by the intermediate product plus in 200g water, 20g sodium carbonate, 15g mistakes is added
Potassium sulfide is reacted under room temperature to complete, after reaction, is added 100mL ethyl acetate and is carried material, concentration removes molten
Agent obtains corresponding intermediate material and is added in another reaction bulb to doing, and adds concentrated hydrochloric acid 200mL, control temperature is at 5 DEG C
Input sodium nitrite 22g carries out diazo-reaction to complete below, then, be warming up to 30 DEG C be pyrolyzed after, add water and
Ethyl acetate is extracted, and is stood, is layered, and ethyl acetate phase is collected, and is removed solvent, is obtained 2,4,5- trifluoro-benzene second of target product
Sour 30g, yield 79%, purity reaches 99.2%.
Embodiment 4
Then it is slow cooling to 5 DEG C in reactor input 2- methyl -4- nitrobenzoic acids 36.5g and glacial acetic acid 150mL
Put into sodium nitrite 26.5g again below, after, then sodium fluoborate 79g is added dropwise, after being added dropwise, control temperature is 0 DEG C~5
DEG C continue fluorination reaction, after middle control confirms that raw material react, then heats up and carry out pyrolysis 30min at 20 DEG C~25 DEG C, then plus
Enter dichloromethane 150mL and water 50mL, after stirring 30min, stands, layering, obtain the dichloromethane solution of II compound containing formula
It is directly used in the reaction of next step, single step yield reaches 93.6%；
The dichloromethane solution of above-mentioned II compound containing formula is put into another reaction bulb, then puts into triethylamine 22g, is controlled
Temperature hereinafter, dichloroacetyl chloride 34g is added dropwise, makes that the reaction was complete at 20 DEG C after completion of dropwise addition, then by material be transferred in ice water into
Row ice solution makes precipitation material, filters, obtains III compound of midbody product formula, single step yield reaches 94.2%；
Obtained III compound of formula is put into reaction bulb again, ethyl alcohol 300mL is added, adds sodium ethoxide 2.5g, is controlled
Temperature processed is reacted at ambient temperature to be made after the reaction was complete, to obtain IV compound of intermediate product formula, then put into 100g glacial acetic acid,
It is warming up to reflux again to be hydrolyzed and decarboxylic reaction, after reaction, 100mL dichloromethane is added and carries material, stand, layering, receipts
Collecting dichloromethane phase, concentration removes dichloromethane and obtains intermediate product to dry, then adds 200g alcohol solvents into the intermediate product,
0.5g palladium carbons are added, being passed through hydrogen and carrying out hydrogenation reduction at room temperature makes reaction 2.5h, and after reaction, concentration removes
It goes alcohol solvent to doing, obtains corresponding intermediate material and be added in another reaction bulb, add glacial acetic acid 200mL, control
Temperature puts into sodium nitrite 20g at 5 DEG C or less and carries out diazo-reaction 1.5h, then, be warming up to 30 DEG C be pyrolyzed after, then add
Enter water and dichloromethane is extracted, stand, be layered, collect dichloromethane phase, removes solvent, obtain target product 2,4,5- tri-
Fluorophenylacetic acid 26g, yield 68%, purity reaches 98.7%.
Embodiment 5
Reactor put into 2- methyl -4- nitrobenzoic acids 36.5g and formic acid 200mL, then, be slow cooling to 8 DEG C with
Under put into sodium nitrite 30g again, after, then sodium fluoborate 78g is added dropwise, after being added dropwise, control temperature 5 DEG C~8 DEG C after
It is continuous to carry out fluorination reaction 2.0h, it after middle control confirms that raw material has reacted, then heats up and carries out pyrolysis 30min at 25 DEG C~30 DEG C, then add
Enter dichloromethane 150mL and water 50mL, after stirring 30min, stands, layering, obtain the dichloromethane solution of II compound containing formula
It is directly used in the reaction of next step, single step yield reaches 93.3%；
The dichloromethane solution of above-mentioned II compound containing formula is put into another reaction bulb, then puts into diethanol amine 24g, is controlled
Temperature processed hereinafter, dichloroacetyl chloride 36g is added dropwise, makes that the reaction was complete, then material is transferred in ice water at 10 DEG C after completion of dropwise addition
Carrying out ice solution makes precipitation material, filters, obtains III compound of midbody product formula, single step yield reaches 94.6%；
Obtained III compound of formula is put into reaction bulb again, ethyl alcohol 300mL is added, adds sodium ethoxide 3.0g, is controlled
Temperature processed is reacted at ambient temperature to be made after the reaction was complete, to obtain IV compound of intermediate product formula, then put into 120g glacial acetic acid,
It is warming up to reflux again to be hydrolyzed and decarboxylic reaction, after reaction, 100mL dichloromethane is added and carries material, stand, layering, receipts
Collecting dichloromethane phase, concentration removes dichloromethane and obtains intermediate product to dry, then adds 200g alcohol solvents into the intermediate product,
1.0g palladium carbons are added, being passed through hydrogen and carrying out hydrogenation reduction at room temperature makes reaction 2.0h, and after reaction, concentration removes
It goes alcohol solvent to doing, obtains corresponding intermediate material and be added in another reaction bulb, add formic acid 150mL, control temperature
Degree puts into sodium nitrite 22g at 10 DEG C or less and carries out diazo-reaction 2.0h, then, be warming up to 25 DEG C keep the temperature and be pyrolyzed after,
It adds water and dichloromethane is extracted, stand, be layered, collect dichloromethane phase, remove solvent, obtain target product 2,4,
5- trifluoro benzene acetic acid 29g, yield 77%, purity reaches 98.8%.
Specific embodiment described in the present invention is only an illustration of the spirit of the invention.Technology belonging to the present invention is led
The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method
In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
It is skilled to this field although present invention has been described in detail and some specific embodiments have been cited
For technical staff, as long as it is obvious that can make various changes or correct without departing from the spirit and scope of the present invention.
Claims (10)
1. one kind 2,4, the preparation method of 5- trifluoro benzene acetic acids, which is characterized in that this approach includes the following steps：
A, under strong acid effect, 2- methyl -4- nitrobenzoic acids are reacted with nitrite after forming diazonium salt dissolving, adds hydrogen
Fluoric acid or borofluoride carry out fluorination reaction, and pyrolysis obtains II compound of formula；
B, in the presence of acid binding agent, II compound of formula and haloacetyl chloride is subjected to acylation reaction, obtain III compound of formula；
C, under the action of alkali metal alcoholates, III compound of formula is reacted with ROH alcoholic solvents, obtains IV compound of formula；
D, IV compound of formula is hydrolyzed under acid system and is handled with decarboxylation, obtain V compound of formula；Again by V chemical combination of formula
Nitro in object carries out diazo-reaction again after reduction, and pyrolysis obtains 2,4,5- trifluoro benzene acetic acid of type I compound；
2. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 1, which is characterized in that strong acid described in step A
Selected from concentrated hydrochloric acid, the concentrated sulfuric acid, formic acid or acetic acid；The nitrite is sodium nitrite or potassium nitrite.
3. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 1, which is characterized in that fluorine boron described in step A
Hydrochlorate is sodium fluoborate；Temperature≤10 DEG C of the fluorination reaction.
4. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 1, which is characterized in that tie up acid described in step B
Agent is selected from one or more of triethylamine, diisopropylethylamine, diethanol amine and pyridine.
5. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 4, which is characterized in that halogenated described in step B
Chloroacetic chloride is selected from dichloroacetyl chloride or trichloro-acetic chloride；The temperature of acylation reaction described in step B is 20 DEG C~35 DEG C.
6. according to the preparation method of 2,4,5- trifluoro benzene acetic acids described in claim 1-5 any one, which is characterized in that step B
Described in acylation reaction carried out in water-insoluble solvent, it is described after reaction be added ice water post-processed, it is described non-aqueous
Soluble solvent is selected from dichloromethane or ethyl acetate.
7. according to the preparation method of 2,4,5- trifluoro benzene acetic acids described in claim 1-5 any one, which is characterized in that step C
Described in alkali metal alcoholates be selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide；The ROH alcohol
Solvent is selected from one or more of methanol, ethyl alcohol and propyl alcohol.
8. according to the preparation method of 2,4,5- trifluoro benzene acetic acids described in claim 1-5 any one, which is characterized in that step D
Described in reduction be specially：
The nitro in V compound of formula is subjected to catalysis under the action of palladium-containing catalyst or persulfide reducing agent and restores to obtain phase
VI compound of midbody product formula answered；
9. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 8, which is characterized in that the palladium-containing catalyst is
Palladium carbon；The persulfide reducing agent is selected from sodium persulfide or over cure potassium.
10. the preparation method of 2,4,5- trifluoro benzene acetic acids according to claim 8, which is characterized in that diazonium described in step D
Changing reaction is specially：
VI compound of formula carries out diazo-reaction with sodium nitrite under≤10 DEG C of temperature condition in glacial acetic acid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851493A (en) * | 2020-11-10 | 2021-05-28 | 杭州臻挚生物科技有限公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN113470757A (en) * | 2021-04-16 | 2021-10-01 | 甘肃省化工研究院有限责任公司 | Thermal risk analysis method of diazotization process |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
| CN103012111A (en) * | 2012-09-12 | 2013-04-03 | 衢州学院 | Preparation method 2,4,5-trifluorophenylacetic acid |
| CN103553900A (en) * | 2013-10-28 | 2014-02-05 | 浙江中欣化工股份有限公司 | Synthesis method of 2,4,5-trifluorophenylacetic acid |
| CN107641130A (en) * | 2017-07-13 | 2018-01-30 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of preparation method of D sulbenicillin sodiums |
-
2018
- 2018-04-28 CN CN201810403640.5A patent/CN108383718A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102548987A (en) * | 2009-07-14 | 2012-07-04 | 江苏迈度药物研发有限公司 | Fluoro-substituted compounds as kinase inhibitors and methods of use thereof |
| CN103012111A (en) * | 2012-09-12 | 2013-04-03 | 衢州学院 | Preparation method 2,4,5-trifluorophenylacetic acid |
| CN103553900A (en) * | 2013-10-28 | 2014-02-05 | 浙江中欣化工股份有限公司 | Synthesis method of 2,4,5-trifluorophenylacetic acid |
| CN107641130A (en) * | 2017-07-13 | 2018-01-30 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of preparation method of D sulbenicillin sodiums |
Non-Patent Citations (7)
| Title |
|---|
| AKIYOSHI MOCHIZUKI ET AL.,: ""Orally active zwitterionic factor Xa inhibitors with long duration of action"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JOHN J. TALLEY: ""OXIDATION OF TERTIARY AMINES BY HEXACHLOROACETONE"", 《TETRAHEDRON LETTERS》 * |
| JUNXING SHI, ET AL.,: ""Reactions of Acid Chlorides/Ketenes with 2-Substituted 4,5-Dihydro-4,4-dimethyl-1,3-thiazoles: Formation of Penam Derivatives"", 《HELVETICA CHIMICA ACTA》 * |
| 国家医药管理局科教司组编: "《制药工艺操作与技术改进》", 31 March 1994, 上海科学普及出版社 * |
| 梁诚: ""芳香族含氟中间体合成技术进展"", 《有机氟化工》 * |
| 王云海等主编: "《环境有机化学》", 31 December 2015, 西安交通大学出版社 * |
| 章思规，辛忠主编: "《精细有机化工制备手册》", 30 April 1994, 科学技术文献出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851493A (en) * | 2020-11-10 | 2021-05-28 | 杭州臻挚生物科技有限公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN113470757A (en) * | 2021-04-16 | 2021-10-01 | 甘肃省化工研究院有限责任公司 | Thermal risk analysis method of diazotization process |
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