CN104262087B - The preparation method of the chloro-4-tolyl acid of a kind of 3,5-bis- - Google Patents
The preparation method of the chloro-4-tolyl acid of a kind of 3,5-bis- Download PDFInfo
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- CN104262087B CN104262087B CN201410436285.3A CN201410436285A CN104262087B CN 104262087 B CN104262087 B CN 104262087B CN 201410436285 A CN201410436285 A CN 201410436285A CN 104262087 B CN104262087 B CN 104262087B
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- chloro
- bis
- methylbenzoic acid
- trimethyl carbinol
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- -1 chloro-4-tolyl Chemical group 0.000 title claims abstract description 75
- 239000002253 acid Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims abstract description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 47
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 39
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000460 chlorine Substances 0.000 claims abstract description 32
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 32
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000047 product Substances 0.000 claims abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- FKTYMPFXOVUJKI-UHFFFAOYSA-N chloro 4-methylbenzoate Chemical compound CC1=CC=C(C(=O)OCl)C=C1 FKTYMPFXOVUJKI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007789 gas Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000004821 distillation Methods 0.000 claims abstract description 6
- 239000012065 filter cake Substances 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000000758 substrate Substances 0.000 claims abstract description 6
- OXLLYJYDLRSBNN-UHFFFAOYSA-N CC(O)(C)C.CC1=CC=C(C(=O)O)C=C1 Chemical compound CC(O)(C)C.CC1=CC=C(C(=O)O)C=C1 OXLLYJYDLRSBNN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 3
- 150000002148 esters Chemical class 0.000 claims abstract description 3
- 238000011049 filling Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 238000000151 deposition Methods 0.000 claims description 3
- 238000010907 mechanical stirring Methods 0.000 claims description 3
- 230000000630 rising effect Effects 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 17
- 238000005660 chlorination reaction Methods 0.000 abstract description 15
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000006193 diazotization reaction Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000004802 cyanophenyl group Chemical group 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- NPYQPFQFFMYBKW-UHFFFAOYSA-N 2-amino-3,5-dichloro-4-methylbenzoic acid Chemical compound ClC1=C(C(C(=O)O)=CC(=C1C)Cl)N NPYQPFQFFMYBKW-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- GBEJAEMDMASLJL-UHFFFAOYSA-N 3,5-dichloro-4-methylbenzoic acid Chemical compound CC1=C(Cl)C=C(C(O)=O)C=C1Cl GBEJAEMDMASLJL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KVPIFZRDXDYGBA-UHFFFAOYSA-N chlorine(1+) Chemical compound [Cl+] KVPIFZRDXDYGBA-UHFFFAOYSA-N 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of 3, the preparation method of the chloro-4-tolyl acid of 5-bis-, comprise step: A, in the reactor filling thionyl chloride, add p-methylbenzoic acid, drip DMF, back flow reaction, steam thionyl chloride under normal pressure, in the middle of the substrate after distillation, drip the trimethyl carbinol, be incubated 50 degree, after stirring 0.5h, obtain p-methylbenzoic acid trimethyl carbinol ester; B, to be dissolved by p-methylbenzoic acid trimethyl carbinol ester methylene dichloride, add aluminum trichloride (anhydrous) and Resorcinol, lucifuge is reacted, and the gas mixture of logical nitrogen and chlorine, obtains the chloro-4-methylbenzoate of 3,5-bis-; C, steam dichloromethane solvent, drip frozen water cancellation aluminum chloride, drip the sodium hydroxide solution alkaline hydrolysis 3 of 10%, the chloro-4-methylbenzoate of 5-bis-, until pH=14, filters, by filtrate hcl acidifying, again filter and by filter cake recrystallizing methanol, obtain 3,5-bis-chloro-4-tolyl acid product.The present invention for raw material, and uses relatively gentle condition with p-methylbenzoic acid simple and easy to get, and through over-churning, chlorination, the steps such as hydrolysis, finally obtain the chloro-4-tolyl acid of 3,5-bis-, substantially increase the security of production process.
Description
Technical field
The present invention relates to the preparation method of the chloro-4-tolyl acid of a kind of 3,5-bis-, belong to technical field of organic synthesis.
Background technology
3,5-bis-chloro-4-tolyl acid is important chemical industry and medicine intermediate, is widely applied in fields such as sterilant, sterilant, medicine intermediates.In recent years, along with each large chemical business has the arrival of patent replacement cycle by oneself, the research for halo chemistry has entered into a brand-new stage.3,5-bis-chloro-4-tolyl acid, as the intermediate having multiple connection site, is widely used, has huge market potential in the exploitation of agricultural chemicals, medicine.The preparation method of 3,5-bis-chloro-4-tolyl acids of current report has following three classes.
The first kind: with 2-amino-4-tolyl acid for raw material, with methylene dichloride, DMF is solvent, uses SULPHURYL CHLORIDE chlorination, obtains 2-amino-4-methyl-3,5-dichlorobenzoic acid, then diazotization is removed amino and obtained the chloro-4-tolyl acid of 3,5-bis-, yield 50-60%.But this kind of method uses diazotization reaction, the danger of operation is increased greatly, in addition, easily produce side reaction owing to reacting itself, yield is difficult to raising and gets on.
Equations of The Second Kind: with 2-amino-4-tolyl acid for raw material, under the existence of hydrochloric acid, directly logical chlorine, obtain 2-amino-4-methyl-3,5-dichlorobenzoic acid, then diazotization obtains 3, the chloro-4-tolyl acid of 5-bis-, finally use toluene to carry out recrystallization, obtain the product that purity is higher, yield about 50%.But the main body reaction of this kind of method is also diazotization reaction, and not as the route of prioritizing selection in production, reaction yield is on the low side, and pollute also larger, production environment is severe.
3rd class: with to methyl cyanophenyl for raw material, will be dissolved in solvent and acidic medium methyl cyanophenyl, drip chlorizating agent at a certain temperature, and control suitable pH value, be obtained by reacting 3,5-bis-chloro-4-methyl cyanophenyl, then at ambient pressure, in system, add alkaline matter, make reacting system PH value remain on certain limit, insulation reaction, hydrolysis obtains 3,5-bis-chloro-4-tolyl acid salt, hcl acidifying obtains the chloro-4-tolyl acid of 3,5-bis-.But this method uses cyanophenyl class as raw material, toxicity is large, and higher to operational requirement, cost of material is higher, although reaction yield is slightly high, and can not as the large route produced.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of 3,5-bis-chloro-4-tolyl acids of a kind of production safety, reacting balance.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
The preparation method of the chloro-4-tolyl acid of a kind of 3,5-bis-, the method comprises the following steps:
A, in the reactor filling thionyl chloride, add p-methylbenzoic acid, drip the DMF (DMF) of catalytic amount, back flow reaction 4-5 hour, reflux temperature 60-70 degree;
Steam thionyl chloride under normal pressure, steam to liquid temperature 100 degree stopping, being cooled to 30 degree; Then in the middle of the substrate after distillation, drip the trimethyl carbinol, be incubated 50 degree, after stirring half hour, normal pressure steams the trimethyl carbinol, obtains p-methylbenzoic acid trimethyl carbinol ester;
B, p-methylbenzoic acid trimethyl carbinol ester methylene dichloride to be dissolved, and add aluminum trichloride (anhydrous) (catalyzer) and Resorcinol (reaction stabilizer), lucifuge is reacted, the gas mixture of logical nitrogen and chlorine, temperature of reaction is 0-35 degree, use the content controlling p-methylbenzoic acid trimethyl carbinol ester in high performance liquid chromatography, when the content of p-methylbenzoic acid trimethyl carbinol ester drops to below 1% or 1% time, reaction terminates, unreacted chlorine alkali liquor absorption, obtain the chloro-4-methylbenzoate of 3,5-bis-;
C, steam dichloromethane solvent, drip frozen water cancellation aluminum chloride, drip the chloro-4-methylbenzoate of sodium hydroxide solution alkaline hydrolysis 3,5-bis-of 10%, until PH reaches 14, filter, in filtrate, drip the hcl acidifying of 4mol/L, when producing without white precipitate in system stop drip, again filter and by filter cake recrystallizing methanol, obtain 3,5-bis-chloro-4-tolyl acid product.
As a preferred technical solution of the present invention, in steps A, the mol ratio of p-methylbenzoic acid and thionyl chloride is 1:1-4, and the mol ratio of p-methylbenzoic acid and the trimethyl carbinol is 1:1-1.5.
As a preferred technical solution of the present invention, in steps A, the mol ratio of p-methylbenzoic acid and thionyl chloride is 1:4, and the mol ratio of p-methylbenzoic acid and the trimethyl carbinol is 1:1.1.
As a preferred technical solution of the present invention, in step B, the mass ratio of methylene dichloride and p-methylbenzoic acid trimethyl carbinol ester is 2-5:1; The mass ratio of aluminum trichloride (anhydrous) and p-methylbenzoic acid trimethyl carbinol ester is 1:15-100; The mass ratio of Resorcinol and p-methylbenzoic acid trimethyl carbinol ester is 1:20-50; The throughput ratio of nitrogen and chlorine is 1-4:1; Temperature of reaction is 25 degree.
As a preferred technical solution of the present invention, in step B, the mass ratio of methylene dichloride and p-methylbenzoic acid trimethyl carbinol ester is 4:1; The mass ratio of aluminum trichloride (anhydrous) and p-methylbenzoic acid trimethyl carbinol ester is 1:20; The mass ratio of Resorcinol and p-methylbenzoic acid trimethyl carbinol ester is 1:50; The throughput ratio of nitrogen and chlorine is 3:1.
As a preferred technical solution of the present invention, in step C, the mol ratio of the chloro-4-methylbenzoate of 3,5-bis-and sodium hydroxide is 1-1.3:1.
As a preferred technical solution of the present invention, in step C, the mol ratio of the chloro-4-methylbenzoate of 3,5-bis-and sodium hydroxide is 1.2:1.
As a preferred technical solution of the present invention, the method comprises the steps: A, on the there-necked flask of 1000 volume parts, installs mechanical stirring additional, add thionyl chloride 700 weight part, p-methylbenzoic acid 200 weight part, drip 3 N, dinethylformamide, temperature rising reflux 5 hours, no longer includes bubble and produces stopping, reflux temperature 68 degree; Steam unnecessary thionyl chloride under normal pressure, steam to liquid temperature 100 degree stopping, being cooled to 30 degree; Then in the middle of the substrate after distillation, drip the trimethyl carbinol 119.6 weight part, be incubated 50 degree, stir 0.5 hour, generate p-methylbenzoic acid trimethyl carbinol ester, normal pressure steams the unnecessary trimethyl carbinol, and steam to liquid temperature 100 degree, it is for subsequent use that logical nitrogen is cooled to room temperature; B, the methylene dichloride of p-methylbenzoic acid trimethyl carbinol ester with 1130 weight parts to be dissolved, add aluminum trichloride (anhydrous) 16 weight part, Resorcinol 5.6 weight part, lucifuge is reacted, the gas mixture of logical nitrogen and chlorine, the throughput ratio of nitrogen and chlorine is 3:1, temperature of reaction is no more than 30 degree, use the content controlling p-methylbenzoic acid trimethyl carbinol ester in high performance liquid chromatography, when the content of p-methylbenzoic acid trimethyl carbinol ester drops to 1%, reaction terminates, obtain the chloro-4-methylbenzoate of 3,5-bis-, unreacted chlorine alkali liquor absorption; C, steam methylene dichloride; First drip a small amount of frozen water cancellation aluminum chloride; Then sodium hydroxide solution 705 weight part of 10% is dripped, until PH=14; Filter, in filtrate, drip the hcl acidifying of 4mol/L, until no longer produce white precipitate in system; Filtering-depositing, filter cake recrystallizing methanol, obtains 3,5-bis-chloro-4-tolyl acid 211 weight part.The volume related in above-mentioned steps or volume, all adopt mL to be unit; The quality related to or weight, all adopt g to be unit.
The beneficial effect adopting technique scheme to produce is:
The present invention take p-methylbenzoic acid as raw material, obtains the chloro-4-tolyl acid of 3,5-bis-successively through over-churning, chlorination, hydrolysis.Compared with prior art, the present invention has abandoned the scheme using cyanophenyl class severe toxicity raw material, makes whole reaction safer.First carry out esterification before chlorination, use ester group adds the steric hindrance on phenyl ring, reaction is more steadily occurred, finally obtains the product that purity is higher, decrease the difficulty of separation and purification.Raw material of the present invention is easy to get, cheap and safety, and product processes is simple, is applicable to amplifying producing, and is the important means of this series products of synthesis.
The present invention is with p-methylbenzoic acid simple and easy to get for raw material, and through over-churning, chlorination, the steps such as hydrolysis, finally obtain the chloro-4-tolyl acid of 3,5-bis-.Be different from the route of diazotizing route and cyanophenyl hydrolysis in the past, the present invention adopts cheap raw material, and uses relatively gentle condition, and substantially increases the security of production process.
Due to the common orientation effect of methyl and carboxyl, 3 and 5 two sites of p-methylbenzoic acid are made more easily to carry out chlorination replacement, under traditional processing condition, direct use chlorinated with chlorine, although also can obtain the chloro-4-tolyl acid of 3,5-bis-, but the content of trichlorine substitution product but will account for very large ratio, and remove cumbersome, the yield which results in direct chlorination is difficult to improve, having little significance of large production.
The present invention adopts first esterification to re-use the method for chlorinated with chlorine, first with the trimethyl carbinol, carboxyl terminal is become the larger group of steric hindrance, and after this prevents 3 and 5 chlorinations generations, on phenyl ring, the continuation of 2 and 6 replaces, and decreases the generation of trichlorine product.Use suitable catalyzer aluminum chloride, and use reaction stabilizer Resorcinol, make the carrying out that chlorination reaction is quick and stable, the selectivity ratios traditional way of reaction is greatly improved.The concentration of chlorine is not easy to control to pass into owing to directly passing into chlorine, the present invention adopts the mode of chlorine and nitrogen parallel feeding, before chlorine reaction just and nitrogen mix, the carrying out of stable reaction can not only be made, improve the output of target product, and avoid the waste of chlorine, alleviate the pressure of tail gas absorption.
Embodiment
Following examples describe the present invention in detail.Various raw material used in the present invention and items of equipment are conventional commercial product, all can be bought by market and directly obtain.The specification of part material of the present invention is as following table:
| Title | Specification |
| P-methylbenzoic acid | Technical pure |
| Thionyl chloride | Technical pure |
| DMF | Analytical pure |
| The trimethyl carbinol | Technical pure |
| Methylene dichloride | Technical pure |
| Aluminum chloride | Analytical pure |
| Resorcinol | Analytical pure |
| Chlorine | Technical pure |
| Sodium hydroxide | Technical pure |
| Hydrochloric acid | Technical pure |
| Methyl alcohol | Technical pure |
The preparation method of the chloro-4-tolyl acid of embodiment 1:3,5-bis-
The present invention take p-methylbenzoic acid as raw material, successively through over-churning, chlorination and hydrolysis, obtains 3,5-bis-chloro-4-tolyl acid product.Reaction equation is:
The preparation method of 3,5-bis-chloro-4-tolyl acids disclosed by the invention, comprises the steps that (volume wherein related to or volume, all adopt mL to be unit; The quality related to or weight, all adopt g to be unit):
A, on the there-necked flask of 1000 volume parts, install mechanical stirring additional, add thionyl chloride 700 weight part, p-methylbenzoic acid 200 weight part, drip 3 DMF, temperature rising reflux 5 hours, no longer include bubble and produce and stop, reflux temperature 68 degree; Steam unnecessary thionyl chloride under normal pressure, steam to liquid temperature 100 degree stopping, being cooled to 30 degree; Then in the middle of the substrate after distillation, drip the trimethyl carbinol 119.6 weight part, be incubated 50 degree, stir 0.5 hour, generate p-methylbenzoic acid trimethyl carbinol ester, normal pressure steams the unnecessary trimethyl carbinol, and steam to liquid temperature 100 degree, it is for subsequent use that logical nitrogen is cooled to room temperature;
B, the methylene dichloride of p-methylbenzoic acid trimethyl carbinol ester with 1130 weight parts to be dissolved, add aluminum trichloride (anhydrous) 16 weight part, Resorcinol 5.6 weight part, lucifuge is reacted, the gas mixture of logical nitrogen and chlorine, the throughput ratio of nitrogen and chlorine is 3:1, temperature of reaction is no more than 30 degree, use the content controlling p-methylbenzoic acid trimethyl carbinol ester in high performance liquid chromatography, when reacting completely after 3.5 hours, the content of p-methylbenzoic acid trimethyl carbinol ester drops to 1%, obtain the chloro-4-methylbenzoate of 3,5-bis-, unreacted chlorine alkali liquor absorption;
C, steam methylene dichloride; First drip a small amount of frozen water cancellation aluminum chloride; Then sodium hydroxide solution 705 weight part of 10% (w/w) is dripped, until PH=14; Filter, in filtrate, drip the hcl acidifying of 4mol/L, until when producing without white precipitate in system stopping dropping, now system PH=3 or below 3; Filtering-depositing, filter cake recrystallizing methanol, obtains 3,5-bis-chloro-4-tolyl acid 211 weight part; Product purity is 98.5%, and yield is 70.1%.
Embodiment 2: the ratio of p-methylbenzoic acid (A) and thionyl chloride (B) chooses research, and related data result gathers as following table:
| A/B (mol ratio) | Starting material left | Product yield |
| 1：1 | 30％ | 20％ |
| 1：3 | 6％ | 50％ |
| 1：4 | Nothing | 70％ |
As seen from the above table, if the thionyl chloride used is very few, raw material p-methylbenzoic acid will remain in a large number, in ensuing esterification process, raw material still can remnants wherein, the purity of the finished product reduces greatly, and after purifying, loss is too much, the usage quantity of thionyl chloride is also too much unsuitable, too much can cause waste.Therefore select p-methylbenzoic acid (A) to be 1:4 with the mol ratio of thionyl chloride (B), use as optimal conditions.
Embodiment 3: the ratio Selecting research of p-methylbenzoic acid (A) and the trimethyl carbinol (C), related data gathers as following table:
| A/C (mol ratio) | Starting material left |
| 1：1 | 3％ |
| 1：1.1 | Nothing |
| 1：1.5 | Nothing |
Because the speed of response of acyl chlorides itself and alcohols is just than comparatively fast, do not need that the trimethyl carbinol is greatly excessive improves speed of response.As seen from the above table, for ensureing the thorough esterification of acyl chlorides, choosing p-methylbenzoic acid (A) with the optimum molar ratio of the trimethyl carbinol (C) is 1:1.1, and reaction result also proves, this ratio is enough to acyl chlorides is transformed completely.
Embodiment 4: the ratio Selecting research of methylene dichloride (D) and p-methylbenzoic acid trimethyl carbinol ester (E), related data gathers as following table:
| D/E (mass ratio) | Product yield |
| 2：1 | 53％ |
| 3：1 | 67％ |
| 4：1 | 70％ |
| 5：1 | 70％ |
As seen from the above table, the consumption of methylene dichloride has larger impact to reaction result, if solvent is very few, raw material does not well disperse, and partial concn is too high, and impurity generates more, yield can be caused too low, and solvent also need not be too much, and the rate of recovery of methylene dichloride itself is not high.Therefore the optimum quality ratio of 4:1 as methylene dichloride (D) and p-methylbenzoic acid trimethyl carbinol ester (E) is chosen.
Embodiment 5: the use quantity research of catalyzer aluminum chloride, result gathers as following table (being as the criterion with the mass ratio of aluminum chloride (F) with p-methylbenzoic acid trimethyl carbinol ester (E)):
| F/E (mass ratio) | Product yield |
| 1：100 | 66％ |
| 1：20 | 70％ |
| 1：15 | 70％ |
As seen from the above table, catalyzer aluminum chloride (F) and the mass ratio of p-methylbenzoic acid trimethyl carbinol ester (E) are best when 1:20, and I haven't seen you for ages excessively makes reaction preference decline, and product yield reduces.
Embodiment 6: the use quantity research of stablizer Resorcinol, result gathers as follows (being as the criterion with the mass ratio of Resorcinol (G) and p-methylbenzoic acid trimethyl carbinol ester (E)):
| G/E (mass ratio) | Product purity |
| 0 | 94％ |
| 1：50 | 98％ |
| 1：20 | 98％ |
From showing above, add the selectivity that reaction stabilizer Resorcinol greatly improves reaction, the yield of the finished product is improve by the generation decreasing impurity, Resorcinol (G) is that 1:50 just can reach good effect with the mass ratio of p-methylbenzoic acid trimethyl carbinol ester (E), does not need to use too much.
Embodiment 7: react whether lucifuge research in step B, result is as following table:
| Whether lucifuge | Product purity |
| Be | 98％ |
| No | 80％ |
As seen from the above table, react whether lucifuge difference is very large.Due to phenyl ring having methyl, if not lucifuge, chlorine under illumination condition, can and phenyl ring on the substitution reaction of methyl generation free radical generate benzyl chlorine, thus affect the purity of product, therefore, necessary lucifuge is reacted.
Embodiment 8: the Selecting research of the flow proportional of nitrogen (H) and chlorine (I), result gathers as following table:
| H/I (throughput ratio) | Product purity |
| 0 | 68％ |
| 1：1 | 76％ |
| 2：1 | 82％ |
| 3：1 | 98％ |
| 4：1 | 92％ |
As seen from the above table, the relative concentration of adjustment chlorine, can improve purity and the yield of product, mainly because the chlorination reaction of chlorine needs to occur according to suitable speed, if react the too fast increase easily causing trichlorine product, and the too low raw material of concentration and a chlorine product residue too much.Selecting the optimal flux of nitrogen (H) and chlorine (I) than being 3:1, the product concentration of very high (98%) can be reached.
Embodiment 9: the Selecting research of chlorination temperature, mainly with the yield of final product for reference to index, result gathers as following table:
| Chlorination reaction temperature | Product yield | Reaction times |
| 0 degree | 65％ | 10h |
| 10 degree | 68％ | 8h |
| 25 degree | 70％ | 4h |
| 35 degree | 67％ | 3h |
As seen from the above table, chlorination reaction temperature is unsuitable too low, too lowly easily causes the reaction times long, and raw material easily cannot not react completely, and too high temperature can cause reaction to gather to carry out simultaneously, and by product increases, and adds the difficulty of aftertreatment.The temperature of reaction of selective chlorination the best be 25 degree can in the shorter reaction times (4h) the inner product yield obtaining higher (70%).
Embodiment 10: because before alkalization, reaction system has a small amount of aluminum chloride, run into water and generate precipitation, cannot judge whether that alkalization completely by the clarity of system, so to adding sodium hydroxide (M) and 3, the mol ratio of the chloro-4-methylbenzoate (N) of 5-bis-is probed into, and result gathers as following table:
| M/N (mol ratio) | Product yield |
| 1：1 | 60％ |
| 1.1：1 | 65％ |
| 1.2：1 | 70％ |
| 1.3：1 | 70％ |
As seen from the above table, the molar weight adding sodium hydroxide (M) during alkalization is 1.2 times of 3,5-bis-chloro-4-methylbenzoate (N) is best, very few words, ester hydrolysis is incomplete, and cause the loss of product, too much words have the burden increasing following acidifying.
Foregoing description only proposes, not as the single restricted condition to its technical scheme itself as the enforceable technical scheme of the present invention.
Claims (8)
1. the preparation method of bis-chloro-4-tolyl acids, is characterized in that: the method comprises the following steps:
A, in the reactor filling thionyl chloride, add p-methylbenzoic acid, drip the DMF DMF of catalytic amount, back flow reaction 4-5 hour, reflux temperature 60-70 degree;
Steam thionyl chloride under normal pressure, steam to liquid temperature 100 degree stopping, being cooled to 30 degree; Then in the middle of the substrate after distillation, drip the trimethyl carbinol, be incubated 50 degree, after stirring half hour, normal pressure steams the trimethyl carbinol, obtains p-methylbenzoic acid trimethyl carbinol ester;
B, p-methylbenzoic acid trimethyl carbinol ester methylene dichloride to be dissolved, and add aluminum trichloride (anhydrous) and Resorcinol, lucifuge is reacted, the gas mixture of logical nitrogen and chlorine, and temperature of reaction is 0-35 degree, use the content controlling p-methylbenzoic acid trimethyl carbinol ester in high performance liquid chromatography, when the content of p-methylbenzoic acid trimethyl carbinol ester drops to below 1% or 1% time, reaction terminates, unreacted chlorine alkali liquor absorption, obtain the chloro-4-methylbenzoate of 3,5-bis-;
C, steam dichloromethane solvent, drip frozen water cancellation aluminum chloride, drip the chloro-4-methylbenzoate of sodium hydroxide solution alkaline hydrolysis 3,5-bis-of 10%, until pH reaches 14, filter, in filtrate, drip the hcl acidifying of 4mol/L, when producing without white precipitate in system stop drip, again filter and by filter cake recrystallizing methanol, obtain 3,5-bis-chloro-4-tolyl acid product.
2. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 1, is characterized in that: in steps A, and the mol ratio of p-methylbenzoic acid and thionyl chloride is 1:1-4, and the mol ratio of p-methylbenzoic acid and the trimethyl carbinol is 1:1-1.5.
3. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 2, is characterized in that: in steps A, and the mol ratio of p-methylbenzoic acid and thionyl chloride is 1:4, and the mol ratio of p-methylbenzoic acid and the trimethyl carbinol is 1:1.1.
4. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 1, is characterized in that: in step B, and the mass ratio of methylene dichloride and p-methylbenzoic acid trimethyl carbinol ester is 2-5:1; The mass ratio of aluminum trichloride (anhydrous) and p-methylbenzoic acid trimethyl carbinol ester is 1:15-100; The mass ratio of Resorcinol and p-methylbenzoic acid trimethyl carbinol ester is 1:20-50; The throughput ratio of nitrogen and chlorine is 1-4:1; Temperature of reaction is 25 degree.
5. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 4, is characterized in that: in step B, and the mass ratio of methylene dichloride and p-methylbenzoic acid trimethyl carbinol ester is 4:1; The mass ratio of aluminum trichloride (anhydrous) and p-methylbenzoic acid trimethyl carbinol ester is 1:20; The mass ratio of Resorcinol and p-methylbenzoic acid trimethyl carbinol ester is 1:50; The throughput ratio of nitrogen and chlorine is 3:1.
6. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 1, is characterized in that: in step C, and the mol ratio of the chloro-4-methylbenzoate of 3,5-bis-and sodium hydroxide is 1-1.3:1.
7. the preparation method of 3,5-bis-chloro-4-tolyl acids according to claim 6, is characterized in that: in step C, and the mol ratio of the chloro-4-methylbenzoate of 3,5-bis-and sodium hydroxide is 1.2:1.
8. the preparation method of bis-chloro-4-tolyl acids, is characterized in that: the method comprises the steps:
A, on the there-necked flask of 1000 volume parts, install mechanical stirring additional, add thionyl chloride 700 weight part, p-methylbenzoic acid 200 weight part, drip 3 DMFs, temperature rising reflux 5 hours, no longer include bubble and produce and stop, reflux temperature 68 degree; Steam unnecessary thionyl chloride under normal pressure, steam to liquid temperature 100 degree stopping, being cooled to 30 degree; Then in the middle of the substrate after distillation, drip the trimethyl carbinol 119.6 weight part, be incubated 50 degree, stir 0.5 hour, generate p-methylbenzoic acid trimethyl carbinol ester, normal pressure steams the unnecessary trimethyl carbinol, and steam to liquid temperature 100 degree, it is for subsequent use that logical nitrogen is cooled to room temperature;
B, the methylene dichloride of p-methylbenzoic acid trimethyl carbinol ester with 1130 weight parts to be dissolved, add aluminum trichloride (anhydrous) 16 weight part, Resorcinol 5.6 weight part, lucifuge is reacted, the gas mixture of logical nitrogen and chlorine, the throughput ratio of nitrogen and chlorine is 3:1, temperature of reaction is no more than 30 degree, use the content controlling p-methylbenzoic acid trimethyl carbinol ester in high performance liquid chromatography, when the content of p-methylbenzoic acid trimethyl carbinol ester drops to 1%, reaction terminates, obtain the chloro-4-methylbenzoate of 3,5-bis-, unreacted chlorine alkali liquor absorption;
C, steam methylene dichloride; First drip a small amount of frozen water cancellation aluminum chloride; Then sodium hydroxide solution 705 weight part of 10% is dripped, until pH=14; Filter, in filtrate, drip the hcl acidifying of 4mol/L, until no longer produce white precipitate in system; Filtering-depositing, filter cake recrystallizing methanol, obtains 3,5-bis-chloro-4-tolyl acid 211 weight part;
The volume related in above-mentioned steps or volume, all adopt mL to be unit; The quality related to or weight, all adopt g to be unit.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1089595A (en) * | 1992-12-01 | 1994-07-20 | 罗姆和哈斯公司 | N-acetonyl benzamide and fungicidal action thereof |
| US6118018A (en) * | 1999-12-06 | 2000-09-12 | Occidental Chemical Corporation | Chlorination and bromination of aromatic compounds at atmospheric pressure |
| CN103224451A (en) * | 2013-05-20 | 2013-07-31 | 山东潍坊润丰化工有限公司 | Method for synthesizing 3,5-dichlorobenzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089595A (en) * | 1992-12-01 | 1994-07-20 | 罗姆和哈斯公司 | N-acetonyl benzamide and fungicidal action thereof |
| US6118018A (en) * | 1999-12-06 | 2000-09-12 | Occidental Chemical Corporation | Chlorination and bromination of aromatic compounds at atmospheric pressure |
| CN103224451A (en) * | 2013-05-20 | 2013-07-31 | 山东潍坊润丰化工有限公司 | Method for synthesizing 3,5-dichlorobenzoic acid |
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