CN105384620A - 3-chloro methyl benzoic acid synthetic method - Google Patents
3-chloro methyl benzoic acid synthetic method Download PDFInfo
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- CN105384620A CN105384620A CN201510951624.6A CN201510951624A CN105384620A CN 105384620 A CN105384620 A CN 105384620A CN 201510951624 A CN201510951624 A CN 201510951624A CN 105384620 A CN105384620 A CN 105384620A
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- benzoic acid
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- chloromethyl benzoic
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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 3-chloro methyl benzoic acid synthetic method, and the specific method is as follows: in zinc chloride, ferric chloride and other Lewis acid catalysts, 3-chloro methyl benzoic acid is synthesized from benzoyl chloride and paraformaldehyde in a solvent in one step. The synthetic method is a one-step reaction, and is simple and easy to control, highly-safe, and high in finished product yield, starting materials are cheap and readily available, the synthetic method is less in waste, the waste can be harmlessly processed, and the synthetic method is clean and environmentally-friendly, and the purity of the 3-chloro methyl benzoic acid prepared by the synthetic method is high.
Description
Technical field
The present invention relates to a kind of preparation method of organic intermediate, be specifically related to the synthetic method of 3-chloromethyl benzoic acid, belong to chemical technology field.
Background technology
3-chloromethyl benzoic acid is a kind of very useful intermediate, can be used for synthesizing many products, as Ketoprofen.At present, the 3-chloromethyl benzoic acid synthetic method recorded in prior art is few, and is nearly all from m-xylene, and first the oxidation of m-xylene list generates 3-tolyl acid, and 3-tolyl acid prepares 3-chloromethyl benzoic acid through Light chlorimation replacement again.
There is significantly not enough and defect in prior art: one, and m-xylene list oxidation selectivity is strong, and two methyl meeting simultaneous oxidations, form m-phthalic acid, reduce purity and the yield of 3-tolyl acid; Its two Light chlorimation substitution reaction uses toxic gas chlorine, need be equipped with extra safety equipment and add security risk; Its three monochloro replaces poor selectivity, 3-(dichloromethyl) phenylformic acid and 3-(trichloromethyl) phenylformic acid is easily produced in chlorination process, by product is many, reduce purity and the yield of product, have a strong impact on the quality of 3-chloromethyl benzoic acid finished product, and the separation of by-products purification procedures generated is complicated and be difficult to purifying, make complicated process of preparation and production efficiency is low, add 3-chloromethyl benzoic acid production cost.
Summary of the invention
For solving the shortcomings and deficiencies such as 3-chloromethyl benzoic acid preparation method in prior art exists product yield and purity is low, purifying process is complicated and security risk is high, the invention provides a kind of novel 3-chloromethyl benzoic acid preparation method, the method is simple and easy to do, security is high, product yield is high, and starting raw material is cheap and easy to get, adopt the 3-chloromethyl benzoic acid purity prepared by this preparation method high.
The present inventor needs to use benzoate in the process of a product development, contriver is with reference to the preparation method of valeric acid chloromethyl ester for this reason, Benzoyl chloride and paraformaldehyde are reacted under Zinc Chloride Anhydrous catalysis, then under condition of high vacuum degree, distills out benzoate.Found that benzoate yield is low, and benzoate impurity is many, purity is low, after carrying out Research on Structural Analysis to impurity, finds to there is a large amount of 3-hydroxymethyl-benzoic acid and 3-chloromethyl benzoic acid product in impurity.Also be a kind of important medicine, chemical intermediate based on 3-chloromethyl benzoic acid, and the defect that exists of prior art and deficiency, for this reason, contriver is studied in detail reaction, to obtain the 3-chloromethyl benzoic acid of high purity, high yield.
The present invention is the technical scheme that actualizing technology object adopts:
A synthetic method for 3-chloromethyl benzoic acid, Benzoyl chloride and paraformaldehyde one-step synthesis 3-chloromethyl benzoic acid in a solvent under lewis acid catalyst.
Described building-up reactions formula is as follows:
Wherein, n=10 ~ 100.
The mol ratio of described lewis acid catalyst, Benzoyl chloride, paraformaldehyde is 0.05 ~ 0.5:1:1 ~ 1.5.
Lewis acid catalyst of the present invention is one or more among aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS, anhydrous stannic chloride, anhydrous stannous chloride, anhydrous cupric chloride, Zinc Chloride Anhydrous, anhydrous manganous chloride.If this reaction is under the condition not having lewis acid catalyst, can not there is chemical reaction in Benzoyl chloride and paraformaldehyde substantially; Many inorganic salt also can this reaction of catalysis, but muriate inorganic salt catalyst better effects if.
Solvent of the present invention is the mixture of one or more among methylene dichloride, chloroform, tetracol phenixin.Described solvent can not contain Sauerstoffatom, nitrogen-atoms, sulphur atom, and Sauerstoffatom, nitrogen-atoms and/or sulphur atom kind solvent, and this kind solvent is unfavorable for the carrying out reacted, and even makes reaction not occur.
The weight of solvent of the present invention is 5 ~ 10 times of Benzoyl chloride weight.
The mol ratio of lewis acid catalyst of the present invention, Benzoyl chloride, paraformaldehyde is 0.05 ~ 0.5:1:1 ~ 1.5, and preferential mol ratio is 0.2:1:1.3.The consumption of starting raw material of the present invention not only can improve the yield of 3-chloromethyl benzoic acid and can reduce production cost, in addition catalyzer Lewis acid consumption of the present invention is little, be 0.05 ~ 0.5:1 with the mol ratio of Benzoyl chloride, the inorganic metal ion introduced because of catalyzer can be reduced.
Temperature of reaction of the present invention is 20 ~ 70 DEG C, reaction times 5 ~ 20h, reaction pressure 0.1 ~ 0.5Mpa.Pressurization can reduce the loss of reaction mass.
Beneficial effect of the present invention is:
1, preparation method of the present invention is single step reaction, synthetic route is short, be convenient to control, avoid m-xylene selective oxidation and the replacement of 3-tolyl acid selectivity, not only increase the purity of 3-chloromethyl benzoic acid, reduce subsequent purification difficulty, simplify operation, also improve 3-chloromethyl benzoic acid yield simultaneously.
2, preparation method of the present invention avoids and uses the contour hazardous reagents of chlorine, and security is high; Preparation method's waste is few simultaneously, and does harmless process, clean environment firendly after being convenient to recovery.
3, preparation method of the present invention is easy to control and polystep reaction can be avoided to reduce yield, and predominant starting material Benzoyl chloride of the present invention is staple commodities simultaneously, and raw material is easy to get, with low cost, and prepared 3-chloromethyl benzoic acid purity is high, yield is high.
4, catalyst levels of the present invention is little, and catalytic efficiency is high, decreases the inorganic metal ion because of catalyzer introducing.
Embodiment
Can better understand the present invention for making those skilled in the art and can be implemented, below in conjunction with specific embodiment, the present invention is further elaborated.
One, embodiment of the present invention part
Embodiment 1
100ml methylene dichloride is dropped into autoclave pressure, add Benzoyl chloride 0.1mol, paraformaldehyde 0.15mol, Zinc Chloride Anhydrous 0.05mol, be filled with nitrogen to 0.3Mpa, in 60 DEG C ~ 70 DEG C reaction times 15h, then room temperature is cooled to, venting nitrogen, reaction solution is put in 100ml frozen water, stir 0.5h, static layering, get lower organic layer and carry out HPLC (HighPerformanceLiquidChromatography, high performance liquid chromatography) analyze, crude product is containing phenylformic acid 2.4% (weight percent), 3-chloromethyl benzoic acid 91.6% (weight percent).
Embodiment 2
60ml chloroform is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.10mol, FERRIC CHLORIDE ANHYDROUS 0.005mol, is filled with nitrogen to 0.5Mpa, in 20 DEG C ~ 25 DEG C reaction times 10h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 3.1%, 3-chloromethyl benzoic acid 90.2%.
Embodiment 3
50ml tetracol phenixin is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.12mol, aluminum trichloride (anhydrous) 0.02mol, is filled with nitrogen to 0.1Mpa, in 55 DEG C ~ 60 DEG C reaction times 20h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 8.2%, 3-chloromethyl benzoic acid 87.7%.
Embodiment 4
70ml chloroform is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.13mol, anhydrous stannous chloride 0.01mol, is filled with nitrogen to 0.4Mpa, in 30 DEG C ~ 40 DEG C reaction times 13h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 9.1%, 3-chloromethyl benzoic acid 86.3%.
Embodiment 5
50ml methylene dichloride and 30ml chloroform are dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.11mol, anhydrous stannic chloride 0.03mol, is filled with nitrogen to 0.2Mpa, in 45 DEG C ~ 55 DEG C reaction times 16h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 4.2%, 3-chloromethyl benzoic acid 92.3%.
Embodiment 6
80ml methylene dichloride is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.15mol, anhydrous cupric chloride 0.025mol, is filled with nitrogen to 0.4Mpa, in 40 DEG C ~ 45 DEG C reaction times 5h, then be cooled to room temperature, venting nitrogen, reaction solution put in 100ml frozen water, stir 0.5h, static layering, gets lower organic layer concentrating under reduced pressure and namely obtains crude product, carries out HPLC analysis to crude product sampling, crude product is containing phenylformic acid 6.6%, 3-chloromethyl benzoic acid 89.1%.
Embodiment 7
80ml methylene dichloride is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.15mol, aluminum trichloride (anhydrous) 0.015mol, is filled with nitrogen to 0.4Mpa, in 25 DEG C ~ 35 DEG C reaction times 8h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 9.6%, 3-chloromethyl benzoic acid 85.2%.
Embodiment 8
50ml chloroform and 20ml tetracol phenixin are dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.13mol, anhydrous manganous chloride 0.02mol, is filled with nitrogen to 0.5Mpa, in 40 DEG C ~ 50 DEG C reaction times 12h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, get lower organic layer and carry out HPLC analysis, crude product is containing phenylformic acid 0.5%, 3-chloromethyl benzoic acid 95.6%.
Two, comparative example's part
Comparative example 1
100ml ethyl acetate is dropped into autoclave pressure, adds Benzoyl chloride 0.1mol, paraformaldehyde 0.1mol, anhydrous zinc dichloride 0.05mol, is filled with nitrogen to 0.5Mpa, in 60 DEG C ~ 70 DEG C reaction times 20h, then room temperature is cooled to, venting nitrogen, puts in 100ml frozen water by reaction solution, stir 0.5h, static layering, take off layer sample and carry out HPLC analysis, 3-chloromethyl benzoic acid content 0.6%, phenylformic acid 98.0%.
Three, experimental sections
Experimental example 1 embodiment 1 ~ 8 synthetic product and the analysis of comparative example 1 synthetic product
Adopt high performance liquid chromatography area normalization method to measure 3-chloromethyl benzoic acid and the benzoic content of by product in embodiment 1 ~ 8 synthetic product and comparative example 1 synthetic product respectively, the results are shown in Table 1.
Table 1 embodiment 1 ~ 8 and comparative example 1 synthetic product detected result
In embodiment 1 ~ 8 synthetic product, the content of 3-chloromethyl benzoic acid is between 85.2% ~ 95.6%, yield is high, the benzoic content of by product is between 0.5% ~ 9.6%, purity is high, and the content of 3-chloromethyl benzoic acid is only 0.6% in comparative example 1 synthetic product, and benzoic content up to the content of 98%, 3-chloromethyl benzoic acid far below embodiment 1 ~ 8, by product phenylformic acid is then higher than embodiment 1 ~ 8.Comparative example 1 difference maximum from embodiment 1 ~ 8 is that reaction system solvent used is different, and the solvent that comparative example 1 uses is the ethyl acetate containing Sauerstoffatom, is unfavorable for the carrying out reacted, the content of target product 3-chloromethyl benzoic acid is reduced.
Claims (8)
1. a synthetic method for 3-chloromethyl benzoic acid, is characterized in that Benzoyl chloride and paraformaldehyde one-step synthesis 3-chloromethyl benzoic acid in a solvent under lewis acid catalyst.
2. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that the chemical equation of described one-step synthesis 3-chloromethyl benzoic acid is as follows:
Wherein, n=10 ~ 100.
3. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that the mol ratio of described lewis acid catalyst, Benzoyl chloride, paraformaldehyde is 0.05 ~ 0.5:1:1 ~ 1.5.
4. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that described lewis acid catalyst is one or more among aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS, anhydrous stannic chloride, anhydrous stannous chloride, anhydrous cupric chloride, Zinc Chloride Anhydrous, anhydrous manganous chloride.
5. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that described solvent is the mixture of one or more among methylene dichloride, chloroform, tetracol phenixin.
6. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 5, is characterized in that the weight of described solvent is 5 ~ 10 times of Benzoyl chloride weight.
7. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that the mol ratio of described lewis acid catalyst, Benzoyl chloride, paraformaldehyde is 0.2:1:1.3.
8. the synthetic method of a kind of 3-chloromethyl benzoic acid according to claim 1, is characterized in that temperature of reaction is 20 ~ 70 DEG C, reaction times 5 ~ 20h, reaction pressure 0.1 ~ 0.5Mpa.
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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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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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