CN109809984B - Simple preparation method of 2, 6-dichlorophenylacetic acid - Google Patents
Simple preparation method of 2, 6-dichlorophenylacetic acid Download PDFInfo
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- dichlorophenylacetic acid
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- cyclohexanone
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- SFAILOOQFZNOAU-UHFFFAOYSA-N 2-(2,6-dichlorophenyl)acetic acid Chemical compound OC(=O)CC1=C(Cl)C=CC=C1Cl SFAILOOQFZNOAU-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 25
- QCAHVKJGHYVLIS-UHFFFAOYSA-N 2,2,6,6-tetrachlorocyclohexan-1-one Chemical compound ClC1(Cl)CCCC(Cl)(Cl)C1=O QCAHVKJGHYVLIS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 230000020477 pH reduction Effects 0.000 claims abstract description 10
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 8
- 238000007033 dehydrochlorination reaction Methods 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- -1 malonic acid diester Chemical class 0.000 claims abstract description 5
- 230000008707 rearrangement Effects 0.000 claims abstract description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000005690 diesters Chemical class 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 claims description 3
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 claims description 3
- 238000006462 rearrangement reaction Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- NFKGQHYUYGYHIS-UHFFFAOYSA-N dibutyl propanedioate Chemical compound CCCCOC(=O)CC(=O)OCCCC NFKGQHYUYGYHIS-UHFFFAOYSA-N 0.000 claims description 2
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- 239000002351 wastewater Substances 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- WKKHCCZLKYKUDN-UHFFFAOYSA-N (2,6-dichlorophenyl)methanol Chemical compound OCC1=C(Cl)C=CC=C1Cl WKKHCCZLKYKUDN-UHFFFAOYSA-N 0.000 description 2
- LBOBESSDSGODDD-UHFFFAOYSA-N 1,3-dichloro-2-(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C=CC=C1Cl LBOBESSDSGODDD-UHFFFAOYSA-N 0.000 description 2
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical group N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XIIULTZDJYYIKR-UHFFFAOYSA-N ethyl 2-(2,6-dichlorophenyl)acetate Chemical compound CCOC(=O)CC1=C(Cl)C=CC=C1Cl XIIULTZDJYYIKR-UHFFFAOYSA-N 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- DMEDNTFWIHCBRK-UHFFFAOYSA-N 1,3-dichloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1Cl DMEDNTFWIHCBRK-UHFFFAOYSA-N 0.000 description 1
- RYMMNSVHOKXTNN-UHFFFAOYSA-N 1,3-dichloro-5-methyl-benzene Natural products CC1=CC(Cl)=CC(Cl)=C1 RYMMNSVHOKXTNN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AOEJUUCUKRUCEF-UHFFFAOYSA-N 2-(2,6-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=CC(Cl)=C1CC#N AOEJUUCUKRUCEF-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012685 metal catalyst precursor Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- LUMVCLJFHCTMCV-UHFFFAOYSA-M potassium;hydroxide;hydrate Chemical compound O.[OH-].[K+] LUMVCLJFHCTMCV-UHFFFAOYSA-M 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a simple and convenient preparation method of 2, 6-dichlorophenylacetic acid, which takes cyclohexanone as an initial raw material to prepare the 2,2,6, 6-tetrachlorocyclohexanone through chlorination reaction with a chlorination reagent, and then prepares the 2, 6-dichlorophenylacetic acid through condensation of malonic acid diester, dehydrochlorination, hydrolysis, rearrangement under an alkaline condition, acidification and decarboxylation. The method has the advantages of cheap and easily-obtained raw materials, safe and simple operation, small amount of waste water, green and environment-friendly process, high product yield and purity and low cost.
Description
Technical Field
The invention relates to a simple preparation method of 2, 6-dichlorophenylacetic acid, belonging to the technical field of chemical and medical engineering.
Background
2, 6-dichlorophenylacetic acid is an important chemical intermediate, and can be used for synthesizing Guanfacine (Guanfacine) and other medicinal and agricultural chemicals.
The preparation method of the 2, 6-dichlorophenylacetic acid mainly comprises the following two methods:
the method comprises the following steps: 2, 6-dichlorotoluene is used as a raw material, and is catalyzed by a complex catalyst formed by transition metal and a ligand (wherein, a transition metal catalyst precursor is preferably palladium chloride, an oxidant is preferably TBP (tert-butyl peroxy ether), and a ligand is preferably Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene)) in the presence of an alcohol and a catalyst and an oxidant to obtain 2, 6-dichlorophenylacetic acid, and the ethyl 2, 6-dichlorophenylacetate is prepared by hydrolysis and acidification, wherein the total yield is 68.4%. See patent document US2013303798, the reaction procedure is described as synthetic route 1.
In the above synthetic route 1, the preparation process of the intermediate ethyl 2, 6-dichlorophenylacetate requires the use of carbon monoxide for high-temperature and high-pressure reaction, and has poor operation safety, high equipment requirement, high cost, and is not favorable for cost reduction and green production of 2, 6-dichlorophenylacetic acid.
The method 2 comprises the following steps: 2, 6-dichlorobenzyl alcohol is used as a raw material, thionyl chloride is chlorinated to prepare 2, 6-dichlorobenzyl chloride, the 2, 6-dichlorobenzyl chloride is substituted by sodium cyanide to prepare 2, 6-dichlorophenylacetonitrile, and the 2, 6-dichlorophenylacetic acid is prepared through hydrolysis and acidification, wherein the total yield is 56-83%. See Phytochemistry, Vol27, No1,51-57,1998 and patent document US2006069142, the reaction procedure is described as scheme 2.
The raw material 2, 6-dichlorobenzyl alcohol in the synthetic route 2 is high in price and not easy to obtain, and the preparation method needs to be replaced by chloro-substituted and sodium cyanide, so that the operation safety is poor, the waste water amount in the process is large, the yield is low, and the industrial production is not facilitated.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple preparation method of 2, 6-dichlorophenylacetic acid. The method has the advantages of cheap and easily-obtained raw materials, low cost, safe and simple operation, small amount of waste water, green and environment-friendly process and high product yield and purity.
The technical scheme of the invention is as follows:
a preparation method of 2, 6-dichlorophenylacetic acid comprises the following steps:
(1) in a solvent, under the catalysis of alkali, cyclohexanone and a chlorinated reagent are subjected to chlorination reaction to prepare 2,2,6, 6-tetrachlorocyclohexanone;
(2) in a solvent, carrying out condensation reaction on the 2,2,6, 6-tetrachlorocyclohexanone obtained in the step (1) and malonic diester under the catalysis of a catalyst; then carrying out dehydrochlorination, hydrolysis and rearrangement reaction in the presence of alkali; finally, obtaining the 2, 6-dichlorophenylacetic acid after acidification and decarboxylation.
According to the present invention, the solvent in step (1) is preferably one or a mixture of two or more of dichloromethane, 1, 2-dichloroethane or chloroform.
According to the invention, the mass ratio of the solvent to the cyclohexanone in the step (1) is preferably 10-30: 1.
Preferably according to the invention, the base in step (1) is one of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate.
Preferably, according to the invention, the chlorinating reagent in step (1) is chlorine gas.
According to the invention, the mole ratio of the chlorinated reagent, the alkali and the cyclohexanone in the step (1) is (4.0-5.0): (4.0-6.0): 1.
Preferably, in the step (1), the chlorination reaction temperature is 0-80 ℃; preferably, the chlorination reaction temperature is 30-60 ℃. The reaction time is 2-8 hours.
According to the invention, the product obtained in step (1) is preferably directly reacted without isolation.
According to the present invention, the solvent in step (2) is preferably one or a mixture of two or more of dichloromethane, 1, 2-dichloroethane or chloroform.
According to the invention, the mass ratio of the solvent in the step (2) to the cyclohexanone in the step (1) is preferably 5-40: 1.
According to the invention, the malonic acid diester in the step (2) is one of dimethyl malonate, diethyl malonate, diisopropyl malonate, di-n-butyl malonate and di-tert-butyl malonate.
According to the invention, the molar ratio of the malonic diester in the step (2) to the cyclohexanone in the step (1) is preferably 1.0-1.5: 1.
Preferably according to the invention, the catalyst in step (2) is an organic base; preferably, the organic base is one or a combination of two of 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN).
Preferably according to the invention, the mass of the catalyst in the step (2) is 5-15% of the mass of the cyclohexanone in the step (1); preferably, the mass of the catalyst is 8-13% of the mass of the cyclohexanone.
Preferably, in the step (2), the condensation reaction temperature is 30-100 ℃; preferably, the condensation reaction temperature is 40-70 ℃. The reaction time is 3-12 hours.
According to the invention, in the step (2), the alkali is sodium hydroxide or potassium hydroxide water solution with the mass concentration of 10-30%.
According to the invention, in the step (2), the molar ratio of the alkali to the malonic diester is 4.0-6.0: 1.
Preferably, in the step (2), the reaction temperature of dehydrochlorination, hydrolysis and rearrangement is 0-100 ℃; preferably, the reaction temperature of dehydrochlorination, hydrolysis and rearrangement is 40-70 ℃. The dehydrochlorination, hydrolysis and rearrangement reaction is a one-pot method, and the total reaction time is 2-8 hours.
According to the invention, the acid used for acidification and decarboxylation in the step (2) is a 30% hydrochloric acid aqueous solution, and the pH value of the system is adjusted to be 1-3 by using acid.
According to the invention, the acidification and decarboxylation reaction temperature in the step (2) is preferably 10-40 ℃. The reaction time is 1-5 hours.
The process of the present invention is depicted as scheme 3 below:
the invention has the technical characteristics and beneficial effects that:
1. the invention takes cyclohexanone as an initial raw material, prepares 2,2,6, 6-tetrachlorocyclohexanone through chlorination reaction, condenses with malonic diester, dehydrochlorinates under alkaline condition, hydrolyzes, rearranges, and prepares 2, 6-dichlorophenylacetic acid through acidification and decarboxylation.
2. In the reaction of 2,2,6, 6-tetrachlorocyclohexanone and malonic diester, the selection and dosage of the catalyst are more important; the catalyst dosage is insufficient, and the final yield is lower even if the reaction is carried out for a long time; improper catalyst selection also reduces the final yield. The specific reaction route, specific raw materials, raw material proportion and reaction conditions of the invention result in high yield and purity of the invention.
3. The raw materials used in the invention are cheap and easily available, and the needed catalyst is cheap and has low overall cost; the method is safe and simple to operate, the used raw materials are high in safety, each step of reaction can be directly carried out for the next step of reaction without separation, and the operation steps are simple; the preparation method can be a one-pot method, has simple preparation steps, small amount of waste water and green and environment-friendly process; the method has high product yield and purity, and the total yield can reach 96.5%.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is given by weight unless otherwise specified. The yields in the examples are all molar yields.
Example 1: preparation of 2,2,6, 6-tetrachlorocyclohexanone
250 g of dichloromethane, 9.9 g (0.1 mol) of cyclohexanone and 60.0 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a reflux condenser and a 10-30% sodium hydroxide aqueous solution absorption device, the mixture is heated, chlorine gas is slowly introduced under the stirring at the temperature of 30-45 ℃, 33.5 g of chlorine gas is actually introduced, the mixture reacts for 5 hours at the temperature of 40-45 ℃ until the reaction is complete, the mixture is cooled to 20 ℃, the mixture is filtered, and a filter cake is washed by dichloromethane for 3 times, 40 g each time. The dichloromethane filtrates were combined, and the solvent was recovered by distillation to obtain 23.5 g of 2,2,6, 6-tetrachlorocyclohexanone as a white powdery solid in a yield of 99.8% and a gas phase purity of 99.5%.
Example 2: preparation of 2,2,6, 6-tetrachlorocyclohexanone
250 g of 1, 2-dichloroethane, 9.9 g (0.1 mol) of cyclohexanone and 60.0 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a reflux condenser and a device for absorbing 10-30% by mass of sodium hydroxide aqueous solution, the mixture is heated, chlorine gas is slowly introduced under stirring at 40-50 ℃, 33.5 g of chlorine gas is actually introduced, the mixture reacts for 3 hours at 45-50 ℃ until the reaction is complete, the mixture is cooled to 20 ℃, the mixture is filtered, and a filter cake is washed 3 times by 1, 2-dichloroethane, 40 g each time. The 1, 2-dichloroethane filtrates were combined and the solvent was recovered by distillation to give 23.6 g of white powdery solid 2,2,6, 6-tetrachlorocyclohexanone in a yield of 99.9% and a gas phase purity of 99.7%.
Example 3: preparation of 2,2,6, 6-tetrachlorocyclohexanone
250 g of dichloromethane, 9.9 g (0.1 mol) of cyclohexanone and 50.0 g of sodium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a reflux condenser and a 10-30% sodium hydroxide aqueous solution absorption device, the mixture is heated, chlorine gas is slowly introduced under the stirring at the temperature of 30-45 ℃, 33.5 g of chlorine gas is actually introduced, the mixture reacts for 5 hours at the temperature of 40-45 ℃ until the reaction is complete, the mixture is cooled to 20 ℃, the mixture is filtered, and a filter cake is washed by dichloromethane for 3 times, 40 g each time. The dichloromethane filtrates were combined, and the solvent was recovered by distillation to obtain 23.1 g of 2,2,6, 6-tetrachlorocyclohexanone as a white powdery solid in a yield of 97.9% and a gas phase purity of 99.8%.
Example 4: preparation of 2, 6-dichlorophenylacetic acid
100 g of methylene chloride, 23.6 g (0.1 mol) of 2,2,6, 6-tetrachlorocyclohexanone prepared in example 2, 14.5 g (0.11 mol) of dimethyl malonate and 0.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a reflux condenser, heated, stirred and reacted for 5 hours at 40-45 ℃, cooled to 20 ℃, added with 100 g of a 20% sodium hydroxide aqueous solution with mass concentration, stirred and reacted for 5 hours at 40-45 ℃, cooled to 20 ℃, layered, the organic phase is back-extracted with water twice, 20 g of water each time, the water phase is combined, acidified with a 30% hydrochloric acid aqueous solution with mass concentration at 20-25 ℃, the pH value of the system is adjusted to 2.0-2.5, acidified and decarboxylated for 2 hours, filtered, 20 g of water is washed, filter cake is dried, 19.6 g of white powdery solid 2, 6-dichlorophenylacetic acid is obtained, the yield is 95.6%, the purity of the liquid phase is 99.7%.
The product nuclear magnetic data is as follows:
1HNMR(400Hz,CDCl3),δ:3.69(s,2H),7.14-7.18(m,1H),7.31-7.33(m,2H),12.39(s,1H)；
example 5: preparation of 2, 6-dichlorophenylacetic acid
100 g of 1, 2-dichloroethane, 23.6 g (0.1 mol) of 2,2,6, 6-tetrachlorocyclohexanone prepared in example 2, 17.5 g (0.11 mol) of diethyl malonate, 1.0 g of DBU were added to a 500 ml four-neck flask equipped with a stirrer, a thermometer and a reflux condenser, heated, stirred and reacted at 60 to 65 ℃ for 3 hours, cooled to 20 ℃, added with 100 g of a 20% by mass aqueous solution of sodium hydroxide, stirred and reacted at 60 to 65 ℃ for 3 hours, cooled to 20 ℃, layered, back-extracted the organic phase with water twice, each time 20 g of water, combined with the aqueous phase, acidified with a 30% by mass aqueous solution of hydrochloric acid at 20 to 25 ℃, adjusted to a pH of 2.0 to 2.5, acidified and decarboxylated for 2 hours, filtered, washed with 20 g of water, filtered, and dried to obtain 19.8 g of 2, 6-dichlorophenylacetic acid as a white powdery solid, the yield is 96.6 percent, and the purity of the liquid phase is 99.8 percent.
Example 6: preparation of 2, 6-dichlorophenylacetic acid
100 g of methylene chloride, 23.6 g (0.1 mol) of 2,2,6, 6-tetrachlorocyclohexanone prepared in example 2, 22.5 g (0.105 mol) of di-tert-butyl malonate and 1.2 g of DBN are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a reflux condenser, heated, stirred and reacted at 40-45 ℃ for 5 hours, cooled to 20 ℃, added with 130 g of potassium hydroxide aqueous solution with the mass concentration of 20%, stirred and reacted at 50-55 ℃ for 5 hours, cooled to 20 ℃, layered, the organic phase is back-extracted with water twice, 20 g of water each time, the water phase is combined, acidified with 30% hydrochloric acid aqueous solution at 20-25 ℃, the pH value of the system is adjusted to 2.0-2.5, acidified and decarboxylated for 2 hours, filtered, 20 g of water is washed, filter cake is dried, 19.2 g of white powdery solid 2, 6-dichlorophenylacetic acid is obtained, the yield is 93.7%, the purity of the liquid phase is 99.6%.
Example 7: preparation of 2, 6-dichlorophenylacetic acid
250 g of dichloromethane, 9.9 g (0.1 mol) of cyclohexanone and 60.0 g of potassium carbonate are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer, a reflux condenser and a 10-30% sodium hydroxide aqueous solution absorption device, the mixture is heated, chlorine gas is slowly introduced under the stirring at the temperature of 30-45 ℃, 33.5 g of chlorine gas is actually introduced, the mixture reacts for 5 hours at the temperature of 40-45 ℃ until the reaction is complete, the mixture is cooled to 20 ℃, the mixture is filtered, and a filter cake is washed by dichloromethane for 3 times, 40 g each time. Mixing dichloromethane filtrates, transferring the dichloromethane filtrate into a 500 ml four-neck flask connected with a stirrer, a thermometer and a reflux condenser, adding 14.5 g (0.11 mol) of dimethyl malonate and 0.8 g of DBU, heating, stirring and reacting at 40-45 ℃ for 5 hours, cooling to 20 ℃, adding 100 g of a 20% sodium hydroxide aqueous solution, stirring and reacting at 40-45 ℃ for 5 hours, cooling to 20 ℃, layering, back-extracting an organic phase with water twice, mixing aqueous phases, acidifying with a 30% hydrochloric acid aqueous solution at 20-25 ℃, adjusting the pH value of the system to 2.0-2.5, acidifying and decarboxylating for 2 hours, filtering, washing a filter cake with 20 g of water, and drying to obtain 19.1 g of white powdery solid 2, 6-dichlorophenylacetic acid, wherein the yield is 93.2%, and the purity of the liquid phase is 99.6%.
Comparative example 1: preparation of 2, 6-dichlorophenylacetic acid
100 g of methylene chloride, 23.6 g (0.1 mol) of 2,2,6, 6-tetrachlorocyclohexanone prepared in example 2, 14.5 g (0.11 mol) of dimethyl malonate, 0.1 g of DBU are added into a 500 ml four-neck flask which is connected with a stirrer, a thermometer and a reflux condenser, the mixture is heated, stirred and reacted for 8 hours at the temperature of 40-45 ℃, cooled to 20 ℃, added with 100 g of a 20% sodium hydroxide aqueous solution with mass concentration, stirred and reacted for 5 hours at the temperature of 40-45 ℃, cooled to 20 ℃, layered, the organic phase is back-extracted with water twice, 20 g of water each time, the aqueous phase is combined, acidified with a 30% hydrochloric acid aqueous solution with the mass concentration between 20-25 ℃, the pH value of the system is adjusted to be 2.0-2.5, acidified and decarboxylated for 2 hours, filtered, 20 g of water is washed, filter cake is dried, 7.3 g of white powdery solid 2, 6-dichlorophenylacetic acid is obtained, the yield of one step is 35, the purity of the liquid phase is 99.2%.
From this comparative example, it is understood that the amount of the catalyst used is important, the amount of the catalyst used is low, and the yield is low even in the case of a long-term reaction.
Claims (17)
1. A preparation method of 2, 6-dichlorophenylacetic acid comprises the following steps:
(1) in a solvent, under the catalysis of alkali, cyclohexanone and a chlorinated reagent are subjected to chlorination reaction to prepare 2,2,6, 6-tetrachlorocyclohexanone; the alkali is one of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate; the chlorinating agent is chlorine;
(2) in a solvent, carrying out condensation reaction on the 2,2,6, 6-tetrachlorocyclohexanone obtained in the step (1) and malonic diester under the catalysis of a catalyst; then carrying out dehydrochlorination, hydrolysis and rearrangement reaction in the presence of alkali; finally, obtaining 2, 6-dichlorophenylacetic acid after acidification and decarboxylation; the alkali is sodium hydroxide or potassium hydroxide aqueous solution with the mass concentration of 10-30%; the catalyst is one or the combination of two of 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN).
2. The process for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the solvent in the step (1) is one or a mixture of two or more of methylene chloride, 1, 2-dichloroethane and chloroform; the mass ratio of the solvent to the cyclohexanone is 10-30: 1.
3. The method for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the molar ratio of the chlorinating agent, the base and the cyclohexanone in the step (1) is (4.0 to 5.0): (4.0 to 6.0): 1.
4. The method for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the chlorination reaction temperature in the step (1) is 0 to 80 ℃.
5. The process for the preparation of 2, 6-dichlorophenylacetic acid according to claim 4, wherein the chlorination reaction temperature is 30 to 60 ℃.
6. The process for the preparation of 2, 6-dichlorophenylacetic acid according to claim 1, wherein the product obtained in the step (1) is directly reacted without isolation.
7. The process for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein in the step (2), the solvent is one or a mixture of two or more of methylene chloride, 1, 2-dichloroethane and chloroform; the mass ratio of the solvent to the cyclohexanone in the step (1) is 5-40: 1.
8. The method for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein in the step (2), the malonic acid diester is one of dimethyl malonate, diethyl malonate, diisopropyl malonate, di-n-butyl malonate, or di-t-butyl malonate; the molar ratio of the malonic diester to the cyclohexanone in the step (1) is 1.0-1.5: 1.
9. The method according to claim 1, wherein the mass of the catalyst in step (2) is 5 to 15% of the mass of the cyclohexanone in step (1).
10. The method for producing 2, 6-dichlorophenylacetic acid according to claim 9, wherein the mass of the catalyst is 8 to 13% of the mass of cyclohexanone.
11. The method for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein in the step (2), the condensation reaction temperature is 30 to 100 ℃.
12. The method for producing 2, 6-dichlorophenylacetic acid according to claim 11, wherein the condensation reaction temperature is 40 to 70 ℃.
13. The process according to claim 1, wherein the reaction temperature for dehydrochlorination, hydrolysis and rearrangement in step (2) is 0 to 100 ℃.
14. The process for the preparation of 2, 6-dichlorophenylacetic acid according to claim 13, wherein the reaction temperatures for said dehydrochlorination, hydrolysis and rearrangement are 40 to 70 ℃.
15. The method for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein in the step (2), the molar ratio of the base to the malonic acid diester is 4.0 to 6.0: 1.
16. The process for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the acid used in the acidification and decarboxylation in the step (2) is a 30% aqueous hydrochloric acid solution, and the pH of the system is adjusted to 1 to 3 using an acid.
17. The process for producing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the acidification and decarboxylation reaction temperature in the step (2) is 10 to 40 ℃.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1358700A (en) * | 1971-02-16 | 1974-07-03 | Quaker Oats Co | Method of producing a tetrachlorinated cyclic ketone |
| JPH01261344A (en) * | 1988-04-12 | 1989-10-18 | Dainippon Ink & Chem Inc | Production of 2,2,6,6-tetracyclohexanone |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1358700A (en) * | 1971-02-16 | 1974-07-03 | Quaker Oats Co | Method of producing a tetrachlorinated cyclic ketone |
| JPH01261344A (en) * | 1988-04-12 | 1989-10-18 | Dainippon Ink & Chem Inc | Production of 2,2,6,6-tetracyclohexanone |
Non-Patent Citations (1)
| Title |
|---|
| 制备N-2，6-二氯苯胺的新工艺路线研究;李洪涛等;《中国药物化学杂志》;19950920;第5卷(第3期);第211-212,215页 * |
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Denomination of invention: A Simple Preparation Method for 2,6-Dichlorophenylacetic Acid Effective date of registration: 20231205 Granted publication date: 20210611 Pledgee: Hengfeng bank Limited by Share Ltd. Dongying branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980069314 |
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