CN105384620B - A kind of synthetic method of 3 chloromethyl benzoic acid - Google Patents
A kind of synthetic method of 3 chloromethyl benzoic acid Download PDFInfo
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- CN105384620B CN105384620B CN201510951624.6A CN201510951624A CN105384620B CN 105384620 B CN105384620 B CN 105384620B CN 201510951624 A CN201510951624 A CN 201510951624A CN 105384620 B CN105384620 B CN 105384620B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/04—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid halides
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Abstract
The present invention relates to a kind of synthetic method of 3 chloromethyl benzoic acid, specific method is chlorobenzoyl chloride and the paraformaldehyde chloromethyl benzoic acid of one-step synthesis 3 in a solvent under the lewis acid catalysts such as zinc dichloride, ferric trichloride.Preparation method of the present invention is single step reaction, and easy easily-controllable, safe, product yield is high, and initiation material is cheap and easy to get, while preparation method discarded object is few, and makees harmless processing, clean environment firendly after reclaiming；3 chloromethyl benzoic acid purity prepared by this method are high.
Description
Technical field
The present invention relates to a kind of preparation method of organic intermediate, and in particular to the synthetic method of 3- chloromethyl benzoic acids,
Belong to chemical technology field.
Background technology
3- chloromethyl benzoic acids are a kind of particularly useful intermediates, can be for many products of synthesis, such as Ketoprofen.Mesh
Before, 3- chloromethyl benzoic acids synthetic method described in prior art is few, and be nearly all from meta-xylene, first between
Dimethylbenzene list oxidation generation 3- methyl benzoic acids, 3- methyl benzoic acids prepare 3- chloromethylbenzene first through Light chlorimation substitution again
Acid.
There is clearly disadvantageous and defect in prior art：First, meta-xylene list oxidation selectivity is not strong, two methyl meetings
Simultaneous oxidation, forms M-phthalic acid, reduces the purity and yield of 3- methyl benzoic acids；Secondly Light chlorimation substitution reaction is used
To toxic gas chlorine, extra safety means need to be equipped with and security risk is added；Thirdly monochloro replaces poor selectivity, in chlorine
3- (dichloromethyl) benzoic acid and 3- (trichloromethyl) benzoic acid are easily produced during change, accessory substance is more, reduce the pure of product
Degree and yield, have a strong impact on the quality of 3- chloromethyl benzoic acid finished products, and the accessory substance generated isolates and purifies complex procedures
And be difficult to purify so that preparation technology is complicated and production efficiency is low, adds 3- chloromethyl benzoic acid production costs.
The content of the invention
To solve, there is product yield in 3- chloromethyl benzoic acids preparation method in the prior art and purity is low, purifying process is multiple
The shortcomings and deficiencies such as miscellaneous and security risk is high, the present invention provides a kind of new 3- chloromethyl benzoic acid preparation methods, the party
Method is simple and easy to do, safe, product yield is high, and initiation material is cheap and easy to get, using the 3- chlorine prepared by the preparation method
Methyl benzoic acid purity is high.
The present inventor needs to use benzoate during a product development, is this invention ginseng
According to the preparation method of valeric acid chloromethyl ester, chlorobenzoyl chloride and paraformaldehyde is set to be reacted under anhydrous zinc chloride catalysis, then in Gao Zhen
Benzoate is distilled out under reciprocal of duty cycle.As a result find that benzoate yield is low, and benzoate impurity is more, purity
It is low, after carrying out Research on Structural Analysis to impurity, find there is a large amount of 3- hydroxymethyl-benzoic acids and 3- chloromethylbenzenes in impurity
Carboxylic acid product.It is also a kind of important medicine, chemical intermediate based on 3- chloromethyl benzoic acids, and prior art lacking of existing
Fall into and not enough, therefore, reaction is studied in detail inventor, to obtain high-purity, 3- chloromethylbenzene first in high yield
Acid.
The present invention is to realize that the technical scheme that technical purpose is used is：
A kind of synthetic method of 3- chloromethyl benzoic acids, chlorobenzoyl chloride and paraformaldehyde are molten under lewis acid catalyst
One-step synthesis 3- chloromethyl benzoic acids in agent.
The synthetic reaction formula is as follows：
Wherein, n=10~100.
The lewis acid catalyst, chlorobenzoyl chloride, the mol ratio of paraformaldehyde are 0.05~0.5:1:1~1.5.
Lewis acid catalyst of the present invention is aluminum trichloride (anhydrous), anhydrous ferric trichloride, anhydrous stannic chloride, anhydrous
One or more among stannous chloride, anhydrous cupric chloride, anhydrous zinc chloride, anhydrous manganous chloride.If this reaction is on no road
Under conditions of Lewis acid catalyst, chlorobenzoyl chloride and paraformaldehyde will not chemically react substantially；Many inorganic salts can also
The reaction is catalyzed, but chloride inorganic salt catalyst effect is more preferable.
Solvent of the present invention is one or more of mixtures among dichloromethane, chloroform, carbon tetrachloride.It is described molten
Agent can not contain oxygen atom, nitrogen-atoms, sulphur atom, and oxygen atom, nitrogen-atoms and/or sulphur atom class solvent, and this kind of solvent is unfavorable
In the progress of reaction, or even prevent reaction from occurring.
The weight of solvent of the present invention is 5~10 times of chlorobenzoyl chloride weight.
Lewis acid catalyst of the present invention, chlorobenzoyl chloride, the mol ratio of paraformaldehyde are 0.05~0.5:1:1~
1.5, preferential mol ratio is 0.2:1:1.3.The consumption of the initiation material of the present invention can not only improve 3- chloromethyl benzoic acids
Yield and production cost can be reduced, catalyst lewis acid consumption of the present invention is small in addition, and the mol ratio with chlorobenzoyl chloride is
0.05~0.5:1, it can reduce because of the inorganic metal ion that catalyst is introduced.
Reaction temperature of the present invention is 20~70 DEG C, 5~20h of reaction time, 0.1~0.5Mpa of reaction pressure.Pressurization
The loss of reaction mass can be reduced.
The beneficial effects of the present invention are:
1st, preparation method of the invention is single step reaction, synthetic route is short, be easy to control, it is to avoid meta-xylene selectivity
Oxidation and 3- methyl benzoic acids selectively replace, and not only increase the purity of 3- chloromethyl benzoic acids, reduce subsequent purification difficult
Degree, simplifies process, while also improving 3- chloromethyl benzoic acid yields.
2nd, preparation method of the invention is avoided using high hazardous reagents such as chlorine, safe；While preparation method
Discarded object is few, and is easy to do harmless processing, clean environment firendly after reclaiming.
3rd, preparation method of the present invention is easily controllable and is avoided that multistep reaction reduces yield, while the main starting of the present invention
Raw material chlorobenzoyl chloride is staple commodities, and raw material is easy to get, with low cost, and prepared 3- chloromethyl benzoic acids purity is high, yield
It is high.
4th, catalyst amount of the present invention is small, high catalytic efficiency, reduces because of the inorganic metal ion that catalyst is introduced.
Embodiment
To allow those skilled in the art to be better understood from the present invention and can be practiced, with reference to specific implementation
The present invention is further elaborated for example.
First, part of the embodiment of the present invention
Embodiment 1
100ml dichloromethane is put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.15mol, anhydrous chlorination is added
Zinc 0.05mol, is filled with nitrogen to 0.3Mpa, in 60 DEG C~70 DEG C reaction time 15h, is then cooled to room temperature, venting nitrogen will
Reaction solution is put into 100ml frozen water, stirs 0.5h, and static layering takes lower organic layer to carry out HPLC (High
Performance Liquid Chromatography, high performance liquid chromatography) analysis, crude product (weight containing benzoic acid 2.4%
Percentage), 3- chloromethyl benzoic acids 91.6% (percentage by weight).
Embodiment 2
60ml chloroforms are put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.10mol, anhydrous ferric trichloride is added
0.005mol, is filled with nitrogen to 0.5Mpa, in 20 DEG C~25 DEG C reaction time 10h, is then cooled to room temperature, venting nitrogen will
Reaction solution is put into 100ml frozen water, stirs 0.5h, and static layering takes lower organic layer to carry out HPLC analyses, crude product first containing benzene
3.1%, 3- of acid chloromethyl benzoic acids 90.2%.
Embodiment 3
50ml carbon tetrachloride is put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.12mol, anhydrous trichlorine is added
Change aluminium 0.02mol, be filled with nitrogen to 0.1Mpa, in 55 DEG C~60 DEG C reaction time 20h, be then cooled to room temperature, venting nitrogen,
Reaction solution is put into 100ml frozen water, 0.5h is stirred, static layering takes lower organic layer to carry out HPLC analyses, and crude product contains benzene
Formic acid 8.2%, 3- chloromethyl benzoic acids 87.7%.
Embodiment 4
70ml chloroforms are put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.13mol, anhydrous stannous chloride is added
0.01mol, is filled with nitrogen to 0.4Mpa, in 30 DEG C~40 DEG C reaction time 13h, is then cooled to room temperature, venting nitrogen will be anti-
Answer liquid to put into 100ml frozen water, stir 0.5h, static layering takes lower organic layer to carry out HPLC analyses, and crude product contains benzoic acid
9.1%, 3- chloromethyl benzoic acid 86.3%.
Embodiment 5
By 50ml dichloromethane and 30ml chloroforms input autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde are added
0.11mol, anhydrous stannic chloride 0.03mol, are filled with nitrogen to 0.2Mpa, in 45 DEG C~55 DEG C reaction time 16h, then cool
To room temperature, venting nitrogen puts into reaction solution in 100ml frozen water, stirs 0.5h, and static layering takes lower organic layer to carry out
HPLC is analyzed, and crude product contains benzoic acid 4.2%, 3- chloromethyl benzoic acids 92.3%.
Embodiment 6
80ml dichloromethane is put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.15mol, anhydrous chlorination is added
Copper 0.025mol, is filled with nitrogen to 0.4Mpa, in 40 DEG C~45 DEG C reaction time 5h, is then cooled to room temperature, venting nitrogen will
Reaction solution is put into 100ml frozen water, stirs 0.5h, and static layering takes lower organic layer to be concentrated under reduced pressure and produces crude product, to crude product
Sampling carries out HPLC analyses, and crude product contains benzoic acid 6.6%, 3- chloromethyl benzoic acids 89.1%.
Embodiment 7
80ml dichloromethane is put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.15mol, anhydrous trichlorine is added
Change aluminium 0.015mol, be filled with nitrogen to 0.4Mpa, in 25 DEG C~35 DEG C reaction time 8h, be then cooled to room temperature, venting nitrogen,
Reaction solution is put into 100ml frozen water, 0.5h is stirred, static layering takes lower organic layer to carry out HPLC analyses, and crude product contains benzene
Formic acid 9.6%, 3- chloromethyl benzoic acids 85.2%.
Embodiment 8
By 50ml chloroforms and 20ml carbon tetrachloride input autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde are added
0.13mol, anhydrous manganous chloride 0.02mol, are filled with nitrogen to 0.5Mpa, in 40 DEG C~50 DEG C reaction time 12h, then cool
To room temperature, venting nitrogen puts into reaction solution in 100ml frozen water, stirs 0.5h, and static layering takes lower organic layer to carry out
HPLC is analyzed, and crude product contains benzoic acid 0.5%, 3- chloromethyl benzoic acids 95.6%.
2nd, comparative example part
Comparative example 1
100ml ethyl acetate is put into autoclave pressure, chlorobenzoyl chloride 0.1mol, paraformaldehyde 0.1mol, anhydrous dichloro is added
Change zinc 0.05mol, be filled with nitrogen to 0.5Mpa, in 60 DEG C~70 DEG C reaction time 20h, be then cooled to room temperature, venting nitrogen,
Reaction solution is put into 100ml frozen water, 0.5h is stirred, static layering removes layer sample and carries out HPLC analyses, 3- chloromethylbenzene first
Acid content 0.6%, benzoic acid 98.0%.
3rd, experimental sections
The synthetic product of 1 embodiment of experimental example 1~8 and the analysis of the synthetic product of comparative example 1
The synthetic product of embodiment 1~8 and the synthesis production of comparative example 1 are determined using high performance liquid chromatography area normalization method respectively
The content of 3- chloromethyl benzoic acids and accessory substance benzoic acid, the results are shown in Table 1 in thing.
The embodiment 1~8 of table 1 and the synthetic product testing result of comparative example 1
The content of 3- chloromethyl benzoic acids is between 85.2%~95.6% in the synthetic product of embodiment 1~8, high income,
The content of accessory substance benzoic acid is between 0.5%~9.6%, and purity is high, and 3- chloromethyl benzoic acids in the synthetic product of comparative example 1
Content be only 0.6%, and the content of benzoic acid be up to 98%, 3- chloromethyl benzoic acids content be far below embodiment 1~8,
And accessory substance benzoic acid is then higher than embodiment 1~8.The difference maximum with embodiment 1~8 of comparative example 1 is used in reaction system
Solvent it is different, the solvent that comparative example 1 is used is the ethyl acetate containing oxygen atom, is unfavorable for the progress of reaction so that target is produced
The content reduction of thing 3- chloromethyl benzoic acids.
Claims (6)
1. a kind of synthetic method of 3- chloromethyl benzoic acids, it is characterised in that chlorobenzoyl chloride and poly under lewis acid catalyst
Formaldehyde one-step synthesis 3- chloromethyl benzoic acids, the lewis acid catalyst, chlorobenzoyl chloride, mole of paraformaldehyde in a solvent
Than for 0.05~0.5:1:1~1.5, the solvent is one or more of mixing among dichloromethane, chloroform, carbon tetrachloride
Thing.
2. a kind of synthetic method of 3- chloromethyl benzoic acids according to claim 1, it is characterised in that the one-step synthesis
The chemical equation of 3- chloromethyl benzoic acids is as follows：
Wherein, n=10~100.
3. a kind of synthetic method of 3- chloromethyl benzoic acids according to claim 1, it is characterised in that the lewis acid
Catalyst is aluminum trichloride (anhydrous), anhydrous ferric trichloride, anhydrous stannic chloride, anhydrous stannous chloride, anhydrous cupric chloride, anhydrous chlorine
Change the one or more among zinc, anhydrous manganous chloride.
4. a kind of synthetic method of 3- chloromethyl benzoic acids according to claim 1, it is characterised in that the weight of the solvent
Measure as 5~10 times of chlorobenzoyl chloride weight.
5. a kind of synthetic method of 3- chloromethyl benzoic acids according to claim 1, it is characterised in that the lewis acid
Catalyst, chlorobenzoyl chloride, the mol ratio of paraformaldehyde are 0.2:1:1.3.
6. the synthetic method of a kind of 3- chloromethyl benzoic acids according to claim 1, it is characterised in that reaction temperature is 20
~70 DEG C, 5~20h of reaction time, 0.1~0.5Mpa of reaction pressure.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2890243A (en) * | 1956-11-15 | 1959-06-09 | Du Pont | Preparation of polychlorobenzoic acids |
| CN101928233A (en) * | 2009-10-23 | 2010-12-29 | 湖北迅达药业股份有限公司 | Cholromethylation method of benzoic acid derivative |
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2015
- 2015-12-17 CN CN201510951624.6A patent/CN105384620B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2890243A (en) * | 1956-11-15 | 1959-06-09 | Du Pont | Preparation of polychlorobenzoic acids |
| CN101928233A (en) * | 2009-10-23 | 2010-12-29 | 湖北迅达药业股份有限公司 | Cholromethylation method of benzoic acid derivative |
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