CN108503531A - A kind of preparation method of 3,3- dimethyl-2-oxo-butyric acids - Google Patents
A kind of preparation method of 3,3- dimethyl-2-oxo-butyric 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
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
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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
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
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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
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
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Abstract
The present invention relates to a kind of preparation methods of 2 ketobutyric acid of 3,3 dimethyl, belong to pharmaceutical intermediate synthesis technical field.In order to solve the problems, such as that existing synthetic route is seriously polluted low with yield, a kind of preparation method of 2 ketobutyric acid of 3,3 dimethyl is provided, this method includes that 3,3 acid dimethyls and halide reagent are carried out halogenating reaction in organic solvent, obtains intermediate product；Be hydrolyzed again be obtained by the reaction hydrolyzed accordingly after product；In the presence of TEMPO catalyst, product carries out oxidation reaction under the action of oxidant after making hydrolysis, using acidification, obtains 3,3 dimethyl of product, 2 ketobutyric acid.The invention avoids noble metal and transiting state metal catalyst mixed catalyst is used, the advantages of reducing the pollution to environment and reduce cost, and still ensure that there is high yield and high-purity.
Description
Technical field
The present invention relates to the preparation methods of one kind 3,3- dimethyl-2-oxo-butyric acids, belong to pharmaceutical intermediate synthetic technology
Field.
Background technology
3,3- dimethyl-2-oxo-butyric acids also known as trimethyl pyruvic acid are mainly used for medicine intermediate, genetic engineering examination
Agent, nourishing additive agent, coating raw material etc..At present very due to the demand of anti-AIDS atazanavir intermediate on international market
Greatly so that wherein mesosome 3, the wide market of 3- dimethyl-2-oxo-butyric acids.
Currently, mainly being closed both at home and abroad for raw material using dichloro pinacolone to the synthesis of 3,3- dimethyl-2-oxo-butyric acids
At corresponding midbody product.
Such as Chinese patent application (publication number：CN1483715A one kind) is disclosed using dichloro pinacolone as raw material, through buck
Hydrolysis obtains 3,3- dimethyl -2- Sodium γ-Hydroxybutrates, then with oxygen or oxygen-containing gas in buck medium and palladium catalyst and bismuth or
In the presence of the compound of bismuth, oxidation obtains 3,3- dimethyl butyrate ketone acid sodium, and further acidification obtains 3,3- dimethyl -2- oxo fourths
Acid
This method is as a result of precious metal palladium as catalyst so that cost is higher, furthermore it need to use high temperature and band
React higher to equipment requirement under the conditions of pressure, security risk is high.
Invention content
The present invention is directed to the above defect existing in the prior art, provides the system of one kind 3,3- dimethyl-2-oxo-butyric acids
Preparation Method solves the problems, such as it is how to provide a kind of new to have without noble metal catalyst and low in the pollution of the environment and yield
High synthesis technology.
The purpose of the present invention is what is be achieved by the following technical programs, one kind 3,3- dimethyl-2-oxo-butyric acids
Preparation method, which is characterized in that this approach includes the following steps：
A, 3,3- acid dimethyls and halide reagent are subjected to halogenating reaction in organic solvent, obtain intermediate product formula I
Compound, the X in the type I compound are halogen；
B, II compound of the formula of being obtained by the reaction is hydrolyzed in type I compound；
C, in the presence of TEMPO catalyst, after II compound of formula carries out oxidation reaction under the action of oxidant, then
Acidified processing obtains III compound of product formula；
Be starting material by using 3,3- acid dimethyls, through with it is halogenated after hydrolyze the halogen atom on halogenated is made to send out again
Life hydrolyzes to form hydroxyl and obtains corresponding intermediate, and halogen substitution here is preferably using chlorine, bromine or iodine etc.；It is follow-up to make
Oxidation reaction process in only need to the catalytic amount containing TEMPO catalyst effect under hydroxyl can be oxidized to corresponding ketone,
It can also achieve the effect that Efficient Conversion, to realize the catalytic body effectively avoided using the mixing such as precious metal palladium and heavy metal bismuth
System, reduces the pollution to environment such as heavy metal, also avoids realizing that reduction is produced into using expensive precious metal catalyst
This advantages of；And the TEMPO catalyst used can realize the effect that repetition is applied mechanically after simple process, be also beneficial to further
Production cost is reduced, TEMPO catalyst here is the abbreviation of tetramethyl piperidine nitrogen oxide catalyst.In addition, using new
Starting material 3, it is big in order to avoid having in reaction system in order to avoid the hydrolysis phenomena of halide reagent after 3- acid dimethyls
The water of amount exists, and by making halogenation carry out in organic solvent, reduces the hydrolysis of halide reagent, allows to preferably improve
The conversion ratio of reaction improves yield and reduces other possible by-products generations, ensure that the purity Coriolis mass requirement of intermediate product,
It is also beneficial to improve the purity Coriolis mass requirement of final product；It, can meanwhile by using 3,3- acid dimethyls to surpass beginning raw material
So that the raw material of each step is all had the advantage of low cost, and whole often step can be made to react by using improved technical process
All have high yield effect.Certainly, the dosage for the raw material that the present invention uses can be according to the fundamental reaction ratio in reaction process
Example is adjusted, such as with 3,3- acid dimethyls for starting material, according to the raw material or midbody product molar equivalent ratio of every step
The comparable dosage of example.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, preferably, halogenation described in step A
Reagent is selected from phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, chlorine, bromine, iodine, triphosgene or carbon tetrachloride, the X and halogenation
Halogen in reagent is corresponding.Halogen substitution can be introduced effectively on methylene, and it is anti-also can further to improve single step
The yield and purification effect answered.Scheme as a further preference preferably makes the halide reagent be selected from thionyl chloride.Raw material has
There is at low cost, and opposite the advantages of being more advantageous to operation.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, preferably, aoxidized described in step C
Reaction further includes being carried out in the presence of catalyst aid, and the catalyst aid is selected from potassium bromide, ferric trichloride, sodium nitrite and hat
One or more of ether.Here catalyst aid typically refers to promote the cocatalyst of TEMPO catalytic activations, allows to more
The good performance for playing activating catalytic, reaches the conversion for keeping raw material more efficient, improves the yield of one-step reaction.As further
Preferred embodiment, the catalyst aid is the mixture of ferric trichloride, sodium nitrite and crown ether, and the ferric trichloride：Nitrous
Sour sodium：The mass ratio of crown ether is 1：0.8~1.2：0.2~0.5.Here crown ether can be 6 ether of 18- crown-s or 15- crown- 5- ethers
Deng.Preferably make catalyst aid ferrous chloride here：Sodium nitrite：The mass ratio of crown ether is 1.0：1.0：0.5.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, preferably, aoxidized described in step C
Agent is selected from one or more of hydrogen peroxide, sodium metaperiodate, sodium hypochlorite, sodium hypobromite, oxygen and air.It can play very well
Oxidation, and a large amount of solid waste is not will produce in reaction process, and also avoid matter of the generation to intermediate product of solid waste
The influence of amount also has the advantages that reaction condition is mild, is conducive to preferably improve the intermediate purity Coriolis mass generated.As more excellent
The scheme of choosing, the oxidant use air.As a result of after this catalyst system and catalyzing, capable of making effectively to use air as oxygen
Agent, basic cost free pressure, the water for advantageously reducing production cost, and being generated in oxidation process will not introduce other miscellaneous
Matter makes more effectively to realize the quality and yield for improving the step product.
It is preferably, organic described in step A in the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids
Solvent is selected from one or more of dichloromethane, ethyl acetate, dichloroethanes, tetrahydrofuran and hexamethylene, and described halogenated
The temperature of reaction is carried out at 25 DEG C or less.It is at low cost to have the advantages that raw material is easy to get, and these solvents are easy to dehydration, enables
It is enough preferably to ensure that reaction system carries out under conditions of anhydrous or substantially anhydrous, preferably avoid halogenating agent to realize
It decomposes, ensures the yield and mass effect of the intermediate product of the list, preferably, the temperature control of the halogenating reaction exists
It is carried out under the conditions of 0 DEG C~5 DEG C.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, preferably, the oxidation in step C is anti-
It should be carried out in one or more of benzene, toluene, dichloroethanes, dichloromethane and benzotrifluoride solvent, the oxidation reaction
Temperature be 30 DEG C~reflux temperature.It is easy to get with raw material, the advantages of small toxicity, has the advantages that reaction condition is mild.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, preferably, hydrolyzed described in step B
It is carried out under the conditions of reaction is existing for inorganic acid or inorganic base, and the temperature of the hydrolysis is 30 DEG C~80 DEG C.Mainly
In order to which hydrolysis and is typically that can adopt for the hydrolysis of halogen at hydroxyl in the presence of acids or bases for step introduces before making halogen
With acidic hydrolysis, basic hydrolysis can also be used, and the halides of halogen therein can also be made effectively to convert the change of an accepted way of doing sth II
Closing object has the effect of high income.As further preferred embodiment, the inorganic acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid
One or more of with polyphosphoric acids；The inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and carbon
One or more of sour potassium.
In the preparation method of above-mentioned 3,3- dimethyl-2-oxo-butyric acids, the dosage of the TEMPO catalyst is generally adopted
With the TEMPO catalyst of catalytic amount, i.e., quite enable the catalyst of addition that reaction is made to carry out, but anti-in order to improve
Efficiency and reaction effect are answered, preferably, the dosage of the TEMPO catalyst is 3,3- acid dimethyl dosages
3wt%~5wt%；The mass ratio of the TEMPO catalyst and catalyst aid is 1：0.5~1：2.0.
The preparation method of the 3,3- dimethyl-2-oxo-butyric acids of the present invention may be used following reaction equation and indicate：
In conclusion compared with prior art, the present invention haing the following advantages：
1. by using being raw material after halogenated with 3,3- acid dimethyls, make the intermediate state product to be formed only need to be
TEMPO or containing efficient conversion can be realized under the action of TEMPO and catalyst aid is avoided using noble metal and transition state gold
Metal catalyst mixed catalyst, the advantages of reducing the pollution to environment and reduce cost, and still ensure that in high yield and
The effect of high-purity.
2. by using TEMPO or containing by using the intermediate formed after halogenated using 3,3- acid dimethyls as raw material
The catalysis of TEMPO and catalyst aid allow to use air as oxidant, have reaction condition mild, production safety risk
Low advantage, and by-product water, environmental pollution is small and avoids the problem that the impurity of oxidant residual itself, makes to have better
The advantages of improving yield and product purity effect.
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
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add dichloromethane 100mL, then, then
Stirring is opened, slow cooling is to 5 DEG C hereinafter, starting the dichloromethane solution that solid phosgene is added dropwise, the solid light that example is added here
For the dosage of gas according to molar equivalent ratio, the amount being added in the present embodiment makes 3,3- acid dimethyls：Solid phosgene rubs
You are than being 1：1.05, after maintaining the temperature at 10 DEG C hereinafter, being added dropwise during being added dropwise, continue the temperature strip at 5 DEG C~10 DEG C
Heat preservation progress halogenating reaction is complete to raw material fundamental reaction under part, and after reaction, control temperature is concentrated at 50 DEG C or less
Solvent is removed, is obtained containing chloro- 3, the 3- acid dimethyls residues of compound of formula I 2-；
Again into residue be added mass percent be 30% sodium hydroxide solution 120g, then, heating 65 DEG C~
Reaction is hydrolyzed in 70 DEG C of heat preservations, after reaction, 50mL dichloromethane is added and is extracted, is layered, collects water layer, directly uses
It is reacted in next step；Here it is preferably to remove impurity to play that dichloromethane, which is added, and carries out extraction, is conducive to preferably carry
The purity Coriolis mass of the high intermediate product；The TEMPO catalyst and 18- crown- 6- ether 1g of 1.75g are added directly into water layer, then adds
Enter toluene 100mL, it is the mixed solvent system of water and toluene to make the solvent of reaction, is stirred for making slowly heating up and control temperature and exists
In the range of 70 DEG C~80 DEG C, the intermediate state product that the air progress supreme step of oxidation reaction is passed through into reaction system has reacted
Entirely, after reaction, catalyst is recovered by filtration, filtrate is stood, and layering removes organic layer, the water layer quality hundred of collection
The pH value for the diluted hydrochloric acid aqueous solution tune system that score is 5% carries out acidification to 1 or less, after acidification, is added two
Chloromethanes carries out extraction extraction product, and the organic layer of collection carries out that processing removing solvent is concentrated under reduced pressure, after drying, finally produced
Object 3,3- dimethyl-2-oxo-butyric acid 45g, yield 80%, gas phase purity content are 98.5%.
Embodiment 2
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add dichloromethane 100mL, then, then
Stirring is opened, slow cooling is to 5 DEG C hereinafter, starting the dichloromethane solution that phosphorus oxychloride is added dropwise, the trichlorine oxygen that example is added here
For the dosage of phosphorus according to molar equivalent ratio, the amount being added in the present embodiment makes 3,3- acid dimethyls：Phosphorus oxychloride is rubbed
You are than being 1：1.12, after maintaining the temperature at 10 DEG C hereinafter, being added dropwise during being added dropwise, continue the temperature condition at 5 DEG C~8 DEG C
Lower heat preservation progress halogenating reaction is complete to raw material fundamental reaction, and after reaction, control temperature carries out concentration at 50 DEG C or less and removes
Solvent is removed, is obtained containing chloro- 3, the 3- acid dimethyls residues of compound of formula I 2-；
The hydrochloric acid solution 100g that mass percent is 20% is added into residue again, then, heats up at 60 DEG C~65 DEG C
Reaction is hydrolyzed in heat preservation, after reaction, 50mL dichloromethane is added and is extracted, is layered, collected organic layer adds water to carry out
Washing extraction, is washed at twice, and water 40mL, concentration is used to remove organic solvent, obtain intermediate residue and be directly used in down every time
The TEMPO catalyst and 15- crown- 5- ether 0.75g of 1.5g are added in direct residue for single step reaction, add toluene 100mL and
Water 80mL, it is the mixed solvent system of water and toluene to make the solvent of reaction, is stirred for making slowly heating up and controlling temperature at 70 DEG C
In the range of~80 DEG C, be passed through into reaction system air carry out the supreme step of oxidation reaction intermediate state product the reaction was complete, instead
After answering, catalyst is recovered by filtration, filtrate is stood, layering, removes organic layer, and the water layer of collection is with mass percent
The pH value of 8% polyphosphoric acids aqueous solution tune system carries out acidification to 1 or less, and after acidification, dichloromethane is added
Alkane carries out extraction extraction product, and the organic layer of collection carries out that processing removing solvent is concentrated under reduced pressure, and after drying, obtains final product 3,
3- dimethyl-2-oxo-butyric acid 45g, yield 76%, gas phase purity content are 98.4%.
Embodiment 3
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add dichloromethane 200mL, then, then
Stirring is opened, slow cooling is to 5 DEG C hereinafter, starting that bromine 80g is added dropwise, dropwise addition maintains the temperature at 5 DEG C hereinafter, dripping in the process
Bi Hou, continuation heat preservation progress halogenating reaction under 3 DEG C~7 DEG C of temperature condition is complete to raw material fundamental reaction, after reaction,
Control temperature carries out concentration at 50 DEG C or less and removes solvent, obtains remaining containing bromo- 3, the 3- acid dimethyls of compound of formula I 2-
Object；
Again into residue be added mass percent be 30% sodium hydroxide solution 120g, then, be warming up to 30 DEG C~
35 DEG C of heat preservations are hydrolyzed that the reaction was complete, after reaction, 50mL dichloromethane are added and is extracted, is layered, collects water layer, directly
It connects for reacting in next step；Here it is preferably to remove impurity to play that dichloromethane, which is added, and carries out extraction, is conducive to more preferable
Raising the intermediate product purity Coriolis mass；The TEMPO catalyst and ferric trichloride 1.75g of 1.75g are added directly into water layer
And sodium nitrite 1.75g, toluene 100mL is added, so that the solvent of reaction is the mixed solvent system of water and toluene, then stir
It mixes, the reaction was complete for the intermediate state product of the dropwise addition liquor natrii hypochloritis progress supreme step of oxidation reaction at ambient temperature, reaction knot
Catalyst is recovered by filtration in Shu Hou, and filtrate is stood, layering, removes organic layer, the water layer mass percent of collection is 5%
The pH value of diluted hydrochloric acid aqueous solution tune system carry out acidification to 1 or less, after acidification, be added toluene 100mL into
Row extraction extraction product, the organic layer of collection, which be concentrated under reduced pressure handling, removes solvent, after drying, obtains final product 3,3- bis-
Methyl -2-Oxobutyric acid 42g, yield 75%, gas phase purity content are 98.5%.
Embodiment 4
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add ethyl acetate 150mL, then, then
Stirring is opened, slow cooling is to 5 DEG C hereinafter, starting that thionyl chloride 25g is added dropwise, dropwise addition maintains the temperature at 5 DEG C hereinafter, drop in the process
After adding, continuation heat preservation progress halogenating reaction under 5 DEG C~10 DEG C of temperature condition is complete to raw material fundamental reaction, reaction knot
Shu Hou, control temperature carry out concentration at 50 DEG C or less and remove solvent, obtain containing chloro- 3, the 3- acid dimethyls of compound of formula I 2-
Residue；
It is then saturated aqueous sodium carbonate 150g is warming up to 50 DEG C~55 that mass percent is added into residue again
DEG C heat preservation is hydrolyzed that the reaction was complete, after reaction, 50mL ethyl acetate is added and is extracted, is layered, collects water layer, directly
For reacting in next step；Here it is preferably to remove impurity to play that ethyl acetate, which is added, and carries out extraction, is conducive to preferably
Improve the purity Coriolis mass of the intermediate product；Directly into water layer be added 1.75g TEMPO catalyst and ferric trichloride 0.8g and
Sodium nitrite 0.8g, 18- crown- 6- ether 0.5g, add benzotrifluoride 120mL, and it is water and benzotrifluoride to make the solvent of reaction
Mixed solvent system is stirred under state, is passed through the intermediate state that air carries out 4 hours supreme steps of oxidation reaction at ambient temperature
The reaction was complete for product, after reaction, catalyst is recovered by filtration, and filtrate is stood, and layering removes organic layer, the water of collection
The pH value for the diluted hydrochloric acid aqueous solution tune system that layer is 5% with mass percent carries out acidification to 1 or less, and acidification terminates
Afterwards, dichloromethane 100mL is added and carries out extraction extraction product, the organic layer of collection, which be concentrated under reduced pressure handling, removes solvent, dries
After dry, final product 3 is obtained, 3- dimethyl-2-oxo-butyric acid 52g, yield 92.8%, gas phase purity content is 99.1%.
Embodiment 5
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add hexamethylene 120mL, then, then are opened
Open stirring, slow cooling is to 5 DEG C hereinafter, and controlling temperature and being passed through chlorine under conditions of 20 DEG C~25 DEG C and carry out halogenating reaction extremely
Raw material fundamental reaction is complete, and after reaction, control temperature carries out concentration at 50 DEG C or less and removes solvent, obtains containing Formulas I
Close chloro- 3, the 3- acid dimethyls residues of object 2-；
It is the potassium hydroxide aqueous solution 130g that mass percent is 25% that mass percent is added into residue again, so
Afterwards, 75 DEG C~80 DEG C heat preservations are warming up to and are hydrolyzed that the reaction was complete, after reaction, 50mL dichloromethane is added and is extracted,
Water layer is collected in layering, is directly used in and is reacted in next step；The TEMPO catalyst and ferric trichloride of 2.5g are added directly into water layer
1.0g and sodium nitrite 0.8g and 15- crown- 5- ether 0.2g, adds dichloroethanes 150mL, and it is water and two to make the solvent of reaction
The mixed solvent system of chloroethanes, is stirred under state, is passed through air at ambient temperature and carries out 3 hours supreme steps of oxidation reaction
Intermediate state product the reaction was complete, after reaction, catalyst is recovered by filtration, filtrate is stood, layering, remove organic layer,
The pH value for the dilute sulfuric acid aqueous solution tune system that the water layer of collection is 5% with mass percent carries out acidification to 1 or less, is acidified
After treatment is added dichloromethane 100mL and carries out extraction extraction product, and the organic layer of collection be concentrated under reduced pressure handling and be removed
Solvent after drying, obtains final product 3,3- dimethyl-2-oxo-butyric acid 51g, yield 91%, and gas phase purity content is
99%.
Embodiment 6
3,3- acid dimethyl 50g are put into the reactor of dried and clean, add dichloromethane 100mL, then, then
Stirring is opened, slow cooling is to 5 DEG C hereinafter, starting the dichloromethane solution that five chlorethoxyfos are added dropwise, the pentachloro- oxygen that example is added here
For the dosage of phosphorus according to molar equivalent ratio, the amount being added in the present embodiment makes 3,3- acid dimethyls：Five chlorethoxyfos rub
You are than being 1：1.2, after maintaining the temperature at 5 DEG C hereinafter, being added dropwise during being added dropwise, continue under 5 DEG C~8 DEG C of temperature condition
Heat preservation progress halogenating reaction is complete to raw material fundamental reaction, and after reaction, control temperature carries out concentration removing at 50 DEG C or less
Solvent is obtained containing chloro- 3, the 3- acid dimethyls residues of compound of formula I 2-；
Again into residue be added mass percent be 30% sodium hydroxide solution 100g, then, heating 70 DEG C~
Reaction is hydrolyzed in 75 DEG C of heat preservations, after reaction, 50mL ethyl acetate is added and is extracted, is layered, collects water layer, directly uses
It is reacted in next step；Here it is preferably to remove impurity to play that ethyl acetate, which is added, and carries out extraction, is conducive to preferably carry
The purity Coriolis mass of the high intermediate product；The TEMPO catalyst and ferric trichloride 1.0g of 1.5g, nitrous acid are added directly into water layer
Sodium 1.2g and 18- crown- 6- ether 0.5g, add dichloromethane 100mL, and it is the mixing of water and dichloromethane to make the solvent of reaction
Dicyandiamide solution is stirred for making slowly heating up and controlling temperature in counterflow condition, and into reaction system, the dioxygen of dropwise addition 20% is water-soluble
Liquid 30g carries out the intermediate state product of the supreme step of oxidation reaction, and the reaction was complete, after reaction, is recovered by filtration catalyst, filtrate into
Row is stood, layering, removes organic layer, the pH value for the phosphoric acid,diluted aqueous solution tune system that the water layer mass percent of collection is 5%
Acidification is carried out to 1 or less, after acidification, ethyl acetate is added and carries out extraction extraction product, the organic layer of collection
It carries out that processing removing solvent is concentrated under reduced pressure, after drying, obtains final product 3,3- dimethyl-2-oxo-butyric acid 50g, yield is
89.2%, gas phase purity content is 99.2%.
Embodiment 7
The preparation method of 3, the 3- dimethyl-2-oxo-butyric acids of the present embodiment is substantially consistent with embodiment 5, differs only in
Its TEMPO is different with the dosage of catalyst aid, and the addition of TEMPO is 2.0g, catalyst aid three specially in the present embodiment
The mixture of iron chloride, sodium nitrite and crown ether, and ferric trichloride is 0.4g, sodium nitrite 0.4g, 18- crown- 6- ethers are
0.2g.Finally obtained product 3,3- dimethyl-2-oxo-butyric acid 50.2g, yield 89.6%, gas phase purity content are
99.2%.
Embodiment 8
The preparation method of 3, the 3- dimethyl-2-oxo-butyric acids of the present embodiment is substantially consistent with embodiment 3, differs only in
Only with TEMPO as catalyst in oxidation reaction process, do not add catalyst aid, and in the present embodiment TEMPO addition
Amount is 2.5g.Finally obtained product 3,3- dimethyl-2-oxo-butyric acid 45g, yield 80.3%, gas phase purity content are
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 3, the preparation method of 3- dimethyl-2-oxo-butyric acids, which is characterized in that this approach includes the following steps：
A, 3,3- acid dimethyls and halide reagent are subjected to halogenating reaction in organic solvent, obtain I chemical combination of intermediate product formula
Object, the X in the type I compound are halogen；
B, II compound of the formula of being obtained by the reaction is hydrolyzed in type I compound；
C, in the presence of TEMPO catalyst, after II compound of formula carries out oxidation reaction under the action of oxidant, using
Acidification obtains III compound of product formula；
2. the preparation method of 3,3- dimethyl-2-oxo-butyric acids according to claim 1, which is characterized in that described in step A
Halide reagent be selected from phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, chlorine, bromine, iodine, triphosgene or carbon tetrachloride, the X with
Halogen in halide reagent is corresponding.
3. the preparation method of 3,3- dimethyl-2-oxo-butyric acids according to claim 1, which is characterized in that described in step C
Oxidation reaction further includes being carried out in the presence of catalyst aid, and the catalyst aid is selected from potassium bromide, ferric trichloride, sodium nitrite
One or more of with crown ether；It is preferred that the crown ether is selected from 18- crown- 6- ethers or 15- crown- 5- ethers.
4. the preparation method of 3,3- dimethyl-2-oxo-butyric acids according to claim 3, which is characterized in that the catalysis helps
Agent is the mixture of ferric trichloride, sodium nitrite and crown ether, and the ferric trichloride：Sodium nitrite：The mass ratio of crown ether is 1：
0.8~1.2：0.2~0.5.
5. the preparation method of 3,3- dimethyl-2-oxo-butyric acids according to claim 1, which is characterized in that described in step C
Oxidant is selected from one or more of hydrogen peroxide, sodium metaperiodate, sodium hypochlorite, sodium hypobromite, oxygen and air.
6. according to the preparation method of 3,3- dimethyl-2-oxo-butyric acids described in claim 1-5 any one, which is characterized in that
Organic solvent described in step A is selected from one or more of dichloromethane, ethyl acetate, dichloroethanes and hexamethylene, and institute
The temperature for stating halogenating reaction is carried out at 25 DEG C or less.
7. according to the preparation method of 3,3- dimethyl-2-oxo-butyric acids described in claim 1-5 any one, which is characterized in that
Oxidation reaction in step C in one or more of benzene, toluene, dichloroethanes, dichloromethane and benzotrifluoride solvent into
The temperature of row, the oxidation reaction is 30 DEG C~reflux temperature.
8. according to the preparation method of 3,3- dimethyl-2-oxo-butyric acids described in claim 1-5 any one, which is characterized in that
It is carried out under the conditions of hydrolysis described in step B is existing for inorganic acid or inorganic base, and the temperature of the hydrolysis is 30
DEG C~80 DEG C.
9. the preparation method of 3,3- dimethyl-2-oxo-butyric acids according to claim 8, which is characterized in that the inorganic acid
Selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and polyphosphoric acids；The inorganic base is selected from sodium hydroxide, potassium hydroxide, carbon
One or more of sour sodium, sodium bicarbonate and potassium carbonate.
10. according to the preparation method of 3, the 3- dimethyl-2-oxo-butyric acids of claim 3 or 4, which is characterized in that described
The dosage of TEMPO catalyst is 3wt%~5wt% of 3,3- acid dimethyl dosages；The TEMPO catalyst and catalyst aid
Mass ratio be 1：0.5~1：2.0.
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