CN114409524A - Preparation method of 2, 6-dichlorophenylacetic acid - Google Patents
Preparation method of 2, 6-dichlorophenylacetic acid Download PDFInfo
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- CN114409524A CN114409524A CN202111677224.2A CN202111677224A CN114409524A CN 114409524 A CN114409524 A CN 114409524A CN 202111677224 A CN202111677224 A CN 202111677224A CN 114409524 A CN114409524 A CN 114409524A
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- dichlorophenylacetic acid
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- dichlorobenzyl bromide
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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 129
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 95
- PDFGFQUSSYSWNI-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1CBr PDFGFQUSSYSWNI-UHFFFAOYSA-N 0.000 claims abstract description 91
- DMEDNTFWIHCBRK-UHFFFAOYSA-N 1,3-dichloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1Cl DMEDNTFWIHCBRK-UHFFFAOYSA-N 0.000 claims abstract description 55
- RYMMNSVHOKXTNN-UHFFFAOYSA-N 1,3-dichloro-5-methyl-benzene Natural products CC1=CC(Cl)=CC(Cl)=C1 RYMMNSVHOKXTNN-UHFFFAOYSA-N 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 50
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 49
- 238000007259 addition reaction Methods 0.000 claims abstract description 46
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims description 50
- 238000005893 bromination reaction Methods 0.000 claims description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 35
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000011777 magnesium Substances 0.000 claims description 28
- 229910052749 magnesium Inorganic materials 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 230000031709 bromination Effects 0.000 claims description 21
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 235000010265 sodium sulphite Nutrition 0.000 claims description 9
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 229960001701 chloroform Drugs 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000007865 diluting Methods 0.000 claims description 4
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 25
- 239000002994 raw material Substances 0.000 abstract description 18
- 238000009776 industrial production Methods 0.000 abstract description 8
- 238000005580 one pot reaction Methods 0.000 abstract description 8
- 239000007818 Grignard reagent Substances 0.000 abstract description 7
- 150000004795 grignard reagents Chemical class 0.000 abstract description 7
- 238000006467 substitution reaction Methods 0.000 abstract description 7
- 239000000376 reactant Substances 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 4
- DGFYECXYGUIODH-UHFFFAOYSA-N Guanfacine hydrochloride Chemical compound Cl.NC(N)=NC(=O)CC1=C(Cl)C=CC=C1Cl DGFYECXYGUIODH-UHFFFAOYSA-N 0.000 abstract description 2
- 229960004746 guanfacine hydrochloride Drugs 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 33
- 239000012535 impurity Substances 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 9
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 231100000614 poison Toxicity 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- 239000003440 toxic substance Substances 0.000 description 4
- WKKHCCZLKYKUDN-UHFFFAOYSA-N (2,6-dichlorophenyl)methanol Chemical compound OCC1=C(Cl)C=CC=C1Cl WKKHCCZLKYKUDN-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001743 benzylic group Chemical group 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- AOEJUUCUKRUCEF-UHFFFAOYSA-N 2-(2,6-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=CC(Cl)=C1CC#N AOEJUUCUKRUCEF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-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
- 238000007605 air drying Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000007033 dehydrochlorination reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 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
- 239000012467 final product Substances 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LBOBESSDSGODDD-UHFFFAOYSA-N 1,3-dichloro-2-(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C=CC=C1Cl LBOBESSDSGODDD-UHFFFAOYSA-N 0.000 description 1
- QCAHVKJGHYVLIS-UHFFFAOYSA-N 2,2,6,6-tetrachlorocyclohexan-1-one Chemical compound ClC1(Cl)CCCC(Cl)(Cl)C1=O QCAHVKJGHYVLIS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000012685 metal catalyst precursor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the field of preparation processes of key intermediates of guanfacine hydrochloride, and particularly discloses a preparation method of 2, 6-dichlorophenylacetic acid, which comprises the following specific steps of firstly, taking 2, 6-dichlorotoluene as an initial raw material, and carrying out substitution reaction on the initial raw material and a bromization reagent to obtain 2, 6-dichlorobenzyl bromide; then, reacting the 2, 6-dichlorobenzyl bromide with magnesium metal to prepare a Grignard reagent, and introducing excessive carbon dioxide into the Grignard reagent to carry out addition reaction to finally obtain the 2, 6-dichlorophenylacetic acid. The raw materials used by the preparation method are simple and easy to obtain, the reaction conditions in the preparation process are mild, and the Grignard reaction and the addition reaction are performed by a one-pot method, so that the reaction steps of the preparation process are few, and the preparation method is low in cost, high in safety and easy for industrial production. Furthermore, the technical process, reactants and reactant consumption of the preparation method are favorable for improving the yield and purity of the target product 2, 6-dichlorophenylacetic acid, the total yield can reach 90%, and the purity can reach 99.5%.
Description
Technical Field
The application relates to the technical field of preparation processes of key intermediates of guanfacine hydrochloride, in particular to a preparation method of 2, 6-dichlorophenylacetic acid.
Background
2, 6-dichlorophenylacetic acid is an important chemical intermediate, and can be used for synthesizing Guanfacine (Guanfacine) as a medicine and other medicine and pesticide products.
The preparation methods of the 2, 6-dichlorophenylacetic acid reported at present mainly comprise the following three methods:
the method comprises the following steps: see patent document US2013303798, which uses 2, 6-dichlorotoluene as a raw material, and reacts with alcohol and carbon monoxide in the presence of an oxidant, and the reaction is catalyzed by a complex catalyst formed by a transition metal and a ligand (wherein, the oxidant is preferably TBP (peroxy-tert-butyl ether), the transition metal catalyst precursor is preferably palladium chloride, and the ligand is preferably Xantphos (4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene)), so as to obtain 2, 6-dichlorophenylacetic acid ethyl ester; then preparing the 2, 6-dichlorophenylacetic acid by hydrolysis and acidification. The yield of 2, 6-dichlorophenylacetic acid obtained was 68.4% compared with the amount of 2, 6-dichlorotoluene used. The reaction sequence is depicted as scheme 1.
In the synthetic route 1, the reaction with carbon monoxide in the preparation process of the intermediate 2, 6-dichlorophenylacetic acid ethyl ester needs to be carried out under the conditions of high temperature and high pressure, so that the operation safety in the reaction process is poor, and the equipment requirement is high; the selected oxidant, transition metal catalyst and ligand lead to high reaction cost, which is not beneficial to the cost reduction and green production of 2, 6-dichlorophenylacetic acid.
The method 2 comprises the following steps: referring to Phytochemistry, Vol27, No1,51-57,1998 and patent document US2006069142, 2, 6-dichlorobenzyl alcohol is used as a raw material, and is subjected to chlorination reaction with thionyl chloride to obtain 2, 6-dichlorobenzyl chloride, and is further subjected to substitution reaction with sodium cyanide to prepare 2, 6-dichlorobenzyl cyanide, and then the 2, 6-dichlorobenzyl cyanide is hydrolyzed and acidified to obtain 2, 6-dichlorophenylacetic acid. The yield of 2, 6-dichlorophenylacetic acid obtained was 56-83% compared to the amount of 2, 6-dichlorobenzyl alcohol. The reaction sequence is depicted as scheme 2.
In the synthesis route 2, the price of the raw material 2, 6-dichlorobenzyl alcohol is high and is not easy to obtain, so that the synthesis cost is high; in the preparation method, the raw materials are subjected to chlorination reaction of thionyl chloride and substitution reaction of sodium cyanide in sequence, the thionyl chloride and the sodium cyanide are toxic substances, so that the safety of reaction operation is poor, the amount of wastewater in the process is large, and the industrial production is not facilitated.
The method 3 comprises the following steps: referring to patent document CN109809984A, 2,6, 6-tetrachlorocyclohexanone is prepared from cyclohexanone as a starting material by chlorination, the obtained 2,2,6, 6-tetrachlorocyclohexanone and malonic diester are subjected to condensation reaction, dehydrochlorination, hydrolysis, rearrangement reaction under alkaline condition, and finally acidification and decarboxylation to prepare 2, 6-dichlorophenylacetic acid. The reaction sequence is depicted as scheme 3.
In the synthetic route 3, the chlorination reaction is carried out by reacting chlorine with cyclohexanone, so that the safety of the operation of the working procedure is poor; the wastewater amount in the dehydrochlorination and acidification decarboxylation processes is large, so that the industrial production is not facilitated.
In conclusion, the existing preparation methods of 2, 6-dichlorophenylacetic acid have the technical problems of poor operation safety, high cost, low yield and the like, so that the preparation methods are not beneficial to industrial production.
Disclosure of Invention
In order to solve the above problems, the present application provides a novel method for producing 2, 6-dichlorophenylacetic acid.
The technical principle of the application is as follows:
a preparation method of 2, 6-dichlorophenylacetic acid is disclosed, wherein the reaction equation of the preparation process is shown in figure 1, firstly 2, 6-dichlorotoluene is used as the starting material, and is subjected to substitution reaction with a bromization reagent to obtain 2, 6-dichlorobenzyl bromide; then, reacting the obtained 2, 6-dichlorobenzyl bromide with magnesium metal to prepare a Grignard reagent, and introducing excessive carbon dioxide into the Grignard reagent to carry out addition reaction to obtain the 2, 6-dichlorophenylacetic acid.
The technical scheme of the application is as follows:
the preparation method of the 2, 6-dichlorophenylacetic acid comprises the following specific steps:
a) bromination reaction
Mixing 2, 6-dichlorotoluene with a bromination reagent and an organic solvent I, and then carrying out bromination reaction at the temperature of 15-80 ℃ to obtain a reaction solution 1; extracting the obtained reaction solution 1, and concentrating an organic phase to obtain 2, 6-dichlorobenzyl bromide;
b) grignard reactions and addition reactions
Diluting the 2, 6-dichlorobenzyl bromide obtained in the step a) by using an organic solvent II, and dropwise adding the diluted 2, 6-dichlorobenzyl bromide into magnesium chips at the temperature of 65-70 ℃ to perform a Grignard reaction to obtain a reaction solution 2;
cooling the obtained reaction liquid 2 to 20-30 ℃, and introducing excessive carbon dioxide for addition reaction to obtain a reaction liquid 3;
and filtering the obtained reaction solution 3 to obtain filtrate, and carrying out crystallization reaction on the filtrate to obtain the 2, 6-dichlorophenylacetic acid.
By adopting the technical scheme, 2, 6-dichlorotoluene is used as an initial raw material, magnesium chips and carbon dioxide are selected to carry out Grignard reaction and addition reaction respectively, and the raw materials belong to mass industrial products, are easy to obtain and are low in price, so that the preparation method of 2, 6-dichlorophenylacetic acid has the advantage of low cost.
Furthermore, the 2, 6-dichlorotoluene is subjected to bromination reaction, Grignard reaction and addition reaction to prepare the 2, 6-dichlorophenylacetic acid, and the whole preparation process has mild reaction conditions, does not need to adopt high-temperature and/or high-pressure reaction conditions and does not involve toxic substances to participate in the reaction, so that the preparation method greatly improves the safety of the reaction operation, namely the technical problem that the preparation method of the 2, 6-dichlorophenylacetic acid in the prior art has poor operation safety is solved.
Furthermore, in the preparation method, the Grignard reaction and the addition reaction are carried out by a one-pot method, so that the reaction steps of the preparation process are less, and the further industrial production is facilitated.
Preferably, the brominating agent is one or more of N-bromosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin and pyridinium hydrogen bromide; in the examples of the present application, only N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin are exemplified, but the use of pyridinium hydrobromide in the preparation method of the present application is not affected;
the organic solvent I is one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, acetonitrile and tetrahydrofuran; the examples of the present application are illustrated with only dichloromethane, acetonitrile and chloroform, but do not affect the use of dichloroethane, carbon tetrachloride and chloroform in the processes of the present application.
By adopting the technical scheme, the bromination reagent and the organic solvent I are selected, so that the 2, 6-dichlorotoluene can be reacted under mild reaction conditions, and the 2, 6-dichlorobenzyl bromide obtained by reacting the bromination reagent with the 2, 6-dichlorotoluene in the organic solvent I is easy to separate from the redundant bromination reagent. The reason for this is probably because all the above brominating reagents can generate substitution reaction with benzylic hydrogen in the above organic solvent I, and have higher selectivity.
More preferably, the brominating agent is N-bromosuccinimide;
the organic solvent I is dichloromethane.
By adopting the technical scheme, the yield of the brominated product 2, 6-dichlorobenzyl bromide can be improved by selecting N-bromosuccinimide as a bromination reagent. The reason for this is probably because the succinimide, which is a by-product generated during the bromination reaction, of N-bromosuccinimide has a very weak nucleophilicity, and therefore, the by-product generated during the reaction can be reduced from further reacting with the generated 2, 6-dichlorobenzyl bromide, thereby increasing the yield of 2, 6-dichlorobenzyl bromide.
The weak-polarity solvent dichloromethane is selected as the organic solvent I, so that the reaction of the N-bromosuccinimide and the 2, 6-dichlorotoluene has higher selectivity, the generation of polybrominated byproducts is reduced, the yield and the purity of the brominated product 2, 6-dichlorobenzyl bromide are improved, the yield can be more than 91.0 percent, and the purity is more than 96.0 percent.
Preferably, the brominating agent is used in an amount of 2, 6-dichlorotoluene: the mol ratio of the brominating agent is 1: 1.1-1.5; the dosage of the organic solvent I is as follows according to 2, 6-dichlorotoluene: 1kg of organic solvent I: 3L.
By adopting the technical scheme, a slightly excessive bromination reagent relative to 2, 6-dichlorotoluene is added in the bromination reaction process of the 2, 6-dichlorotoluene, so that the excessive bromination reagent can promote the reaction to be carried out in the forward direction, the raw material 2, 6-dichlorotoluene is completely reacted, and the yield of 2, 6-dichlorobenzyl bromide can be improved; on the other hand, the appropriate excess of the brominating agent can reduce the generation of polybrominated by-products, and the purity of the 2, 6-dichlorobenzyl bromide can be obviously improved by matching with the dosage of the organic solvent I. Due to the adoption of the dosage of the scheme, the obtained 2, 6-dichlorobenzyl bromide has high raw material conversion rate and few impurities, and the difficulty in purifying the 2, 6-dichlorobenzyl bromide can be further reduced.
More preferably, the brominating agent is used in an amount of 2, 6-dichlorotoluene: the mol ratio of the brominating agent is 1: 1.2.
by adopting the technical scheme, on the premise of selecting the bromination reagent as N-bromosuccinimide and the organic solvent I as dichloromethane, the use amount of the bromination reagent is selected to ensure that the purity and the yield of the 2, 6-dichlorobenzyl bromide obtained by the bromination reaction are optimal, the purity of the bromination product 2, 6-dichlorobenzyl bromide is more than 99.0 percent, and the molar yield can reach 95 percent.
Preferably, the extractant used in the extraction process of the reaction solution 1 is a sodium sulfite aqueous solution with the mass percent concentration of 10%; the molar amount of the sodium sulfite aqueous solution with the mass percentage concentration of 10% is the same as that of the excessive brominating reagent, and the molar amount of the excessive brominating reagent is the theoretical residual amount of the brominating reagent after the brominating reaction is finished.
By adopting the technical scheme, the sodium sulfite aqueous solution with the mass percentage concentration of 10% is used as the extracting agent and can react with the excessive brominating agent to reduce the excessive brominating agent into the water-soluble by-product, so that the water-soluble by-product can be easily removed from the system in the subsequent treatment process, the purity of the 2, 6-dichlorobenzyl bromide is obviously improved, and the appearance of the product can be white or similar to white.
Preferably, the step b) of the grignard reaction and the crystallization reaction in the addition reaction are specifically as follows:
filtering the obtained reaction liquid 3 to obtain filtrate, concentrating under reduced pressure, and adding methanol to dissolve to obtain reaction liquid 4; and then dropwise adding 2-4mol/L hydrochloric acid aqueous solution into the reaction solution 4, adjusting the pH of the reaction solution 4 to be less than 2, performing crystallization reaction, and after dropwise adding is finished, performing pressure suction filtration to obtain 2, 6-dichlorophenylacetic acid.
By adopting the technical scheme, the product obtained by the addition reaction is subjected to crystallization reaction in methanol and hydrochloric acid aqueous solution, the product is completely dissolved by using methanol, and the solubility of the 2, 6-dichlorophenylacetic acid can be gradually reduced by further combining water in the hydrochloric acid aqueous solution and the methanol as a crystallization solvent; the pH value of the solution is gradually adjusted to be less than 2 by adopting 2-4mol/L hydrochloric acid aqueous solution in a dropwise adding mode, so that the 2, 6-dichlorophenylacetic acid is gradually separated out from the solution until the pH value of the solution is less than 2, the complete separation of the 2, 6-dichlorophenylacetic acid is completed, the purity of the target product 2, 6-dichlorophenylacetic acid is obviously improved, and the purity is more than 99.5%.
Preferably, the concentration of the hydrochloric acid aqueous solution is 2mol/L, and the dosage of the 2mol/L hydrochloric acid aqueous solution is as follows: the volume ratio of methanol is 2: 1.
by adopting the technical scheme, the concentration of the hydrochloric acid aqueous solution can realize the complete precipitation of the 2, 6-dichlorophenylacetic acid under the condition of the minimum using amount of the hydrochloric acid aqueous solution, so that the material cost is reduced, and the industrial production application is facilitated.
Preferably, in the step b) of Grignard reaction and addition reaction, the 2, 6-dichlorobenzyl bromide obtained in the step a) is diluted to 1.0-2.5mol/L by using an organic solvent II;
the organic solvent II is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether and methyl tert-butyl ether;
the dosage of the magnesium chips is as follows according to 2, 6-dichlorobenzyl bromide: the molar ratio of the magnesium chips is 1: (2-6).
By adopting the technical scheme, the Grignard reaction is promoted to proceed towards the forward direction by the 1.0-2.5 mol/L2, 6-dichlorobenzyl bromide due to the relatively high concentration in the dropping process, and the content of other coupling impurities generated by further reaction of the excessive 2, 6-dichlorobenzyl bromide and the Grignard reagent in the reaction process can be reduced without adopting a particularly high concentration, so that the yield of the target product 2, 6-dichlorophenylacetic acid is improved.
Furthermore, the organic solvent II has a great influence on the generation of coupling impurities in the reaction process, so that the organic solvent II can further obtain high yield on the premise of ensuring that the purity of the target product 2, 6-dichlorophenylacetic acid meets the requirement (> 99.0%); the use amount of the magnesium chips can ensure the complete reaction and reduce the cost of the magnesium chips in the Grignard reaction.
More preferably, in the step b) of the Grignard reaction and the addition reaction, the 2, 6-dichlorobenzyl bromide obtained in the step a) is diluted to 2.0mol/L by using an organic solvent II;
the organic solvent II is 2-methyltetrahydrofuran;
the dosage of the magnesium chips is as follows according to 2, 6-dichlorobenzyl bromide: the molar ratio of the magnesium chips is 1: 3.
by adopting the technical scheme, the dilution concentration of the 2, 6-dichlorobenzyl bromide, the organic solvent II and the consumption of the magnesium chips can be used for obtaining the highest molar yield which can reach 95 percent under the condition of meeting the purity (> 99.0%) of the 2, 6-dichlorophenylacetic acid, namely the total yield of the target product 2, 6-dichlorophenylacetic acid can reach 90 percent. Meanwhile, the use amount can reduce the reaction cost of the Grignard reaction and the addition reaction, and is beneficial to the industrial application of the preparation method.
In summary, the present application has the following beneficial effects:
according to the preparation method of 2, 6-dichlorophenylacetic acid, 2, 6-dichlorotoluene is used as an initial material, and a brand-new preparation method of 2, 6-dichlorophenylacetic acid is developed: namely, the 2, 6-dichlorotoluene is subjected to one-pot reaction of bromination reaction, Grignard reaction and addition reaction in sequence in one pot, and the total two-step reaction is adopted to prepare the 2, 6-dichlorophenylacetic acid. 2, 6-dichlorotoluene is selected as an initial raw material, and magnesium chips and carbon dioxide are selected to perform a Grignard reaction and an addition reaction respectively, and the raw material is simple and easy to obtain and has low price, so that the preparation method of the application has low cost. Furthermore, the reaction process conditions of the bromination reaction, the Grignard reaction and the addition reaction are mild, and the means of influencing the operation safety, such as high temperature and/or high pressure conditions or the participation of toxic substances in the reaction and the like, are not needed, so that the safety of the reaction process is greatly improved; the Grignard reaction and the addition reaction adopt a one-pot method, so that the reaction steps of the preparation process are less, and the further industrial application of the preparation process is facilitated. Therefore, the preparation method has the advantages of low cost, high operation safety and few reaction steps, and can be further applied to industrial production.
Furthermore, in the preparation method of 2, 6-dichlorophenylacetic acid, a bromination reagent selected in the bromination reaction is subjected to substitution reaction with benzylic hydrogen of 2, 6-dichlorotoluene in an organic solvent I, so that the method has high selectivity, and the yield and the purity of the bromination product 2, 6-dichlorobenzyl bromide are improved; the use amount of the selected brominating agent and the organic solvent I are matched, and a sodium sulfite aqueous solution with the mass percentage concentration of 10% is adopted as an extracting agent to react with the redundant brominating agent, so that the yield and the purity of the final product of the brominating reaction, namely the 2, 6-dichlorobenzyl bromide, can be remarkably improved, and the 2, 6-dichlorobenzyl bromide can obtain higher yield on the premise that the purity is more than 99%, and the highest yield can reach 95%.
Further, according to the preparation method of 2, 6-dichlorophenylacetic acid, when the Grignard reagent is prepared, the selected organic solvent II and the reaction condition for diluting the 2, 6-dichlorobenzyl bromide to a specific concentration can both reduce the generation of coupling impurities and the dissolution enrichment effect, so that the purity of the target product 2, 6-dichlorophenylacetic acid is improved; furthermore, the proper magnesium chip dosage can reduce the cost of the Grignard reaction while ensuring the complete reaction; furthermore, methanol and 2-4mol/L hydrochloric acid aqueous solution are adopted to carry out crystallization reaction on the product after the Grignard reaction and the addition reaction, so that 2, 6-dichlorophenylacetic acid can be effectively collected, the reaction condition of the crystallization reaction is obviously improved, the purity of the 2, 6-dichlorophenylacetic acid is improved, the yield of the 2, 6-dichlorophenylacetic acid can reach 95 percent at most, and the purity can reach 99.5 percent.
According to the preparation method of the 2, 6-dichlorophenylacetic acid, the design of the bromination reaction, the Grignard reaction and the addition reaction and the selection and the dosage of each reactant are combined, so that the total yield and the purity of the target product 2, 6-dichlorophenylacetic acid are remarkably improved, and the maximum total yield of the target product 2, 6-dichlorophenylacetic acid can reach 90% compared with the raw material 2, 6-dichlorotoluene.
In summary, the preparation method has low cost, high reaction safety, few reaction steps and high yield and purity of the target product, so that the preparation method has a high value of industrial application.
Drawings
FIG. 1 is a reaction equation schematic of the preparation of 2, 6-dichlorophenylacetic acid provided herein;
FIG. 2 is an HPLC plot of 2, 6-dichlorobenzyl bromide obtained in step a) of example 1 of the present application;
FIG. 3 is an HPLC chart of 2, 6-dichlorophenylacetic acid obtained in step b) of example 1 of the present application.
Detailed Description
The starting materials used in the examples of the present application are commercially available except for the following 2, 6-dichlorotoluene.
2, 6-dichlorotoluene, 99 wt.%, Shanghai Tantake Techno technologies, Inc.
The nmr used in the examples of the present application, nmr, 400MHz bruke.
In the examples of the present application, a High Performance Liquid Chromatograph (HPLC), agilent 1260, was used for detecting 2, 6-dichlorobenzyl bromide and 2, 6-dichlorophenylacetic acid under the following detection conditions:
the purities of the 2, 6-dichlorobenzyl bromide and the 2, 6-dichlorophenylacetic acid in the examples of the application are calculated by adopting an area normalization method according to the peak areas of the obtained HPLC chart; the molar yields of 2, 6-dichlorobenzyl bromide and 2, 6-dichlorophenylacetic acid were calculated as: the yield was 100% actual/theoretical yield compared to the starting material 2, 6-dichlorotoluene.
Examples
Example 1
A preparation method of 2, 6-dichlorophenylacetic acid comprises the following specific steps:
a) bromination reaction
161g of 2, 6-dichlorotoluene (1.0mol), 213.6g N-bromosuccinimide (1.2mol, molar ratio of 2, 6-dichlorotoluene is 1.2: 1) and 500mL of dichloromethane (amount ratio of 2, 6-dichlorotoluene is 1 kg: 3L) are added into a reaction vessel 1 with a condensing device, the mixture is stirred at the controlled temperature of 15-80 ℃, and reaction is carried out for 24h to obtain a reaction solution 1; under the condition of keeping stirring, 252g of sodium sulfite aqueous solution with the mass percentage concentration of 10% (wherein the molar weight of sodium sulfite is 0.2mol) is added into the reaction solution 1, after 1.5h of reaction, standing and liquid separation are carried out, an organic phase is taken for decompression and concentration to obtain a white-like solid crude product 1, the white-like solid crude product 1 is subjected to forced air drying for 5-6 hours at the temperature of 70-80 ℃ of an oven to obtain 228g of the white-like solid product 1, and the purity of the white-like solid product is 99.5% according to an HPLC chart.
Taking the white-like solid product 1 for nuclear magnetic resonance detection, wherein the obtained nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (400MHz, cdcl3) δ 7.33(d, J ═ 8.0Hz,2H),7.22-7.13(m,1H),4.76(s,1H). The bromination reaction in step a) gave 2, 6-dichlorobenzyl bromide in a molar yield of 95%.
b) Grignard reaction and addition reaction
Dissolving 228g of 2, 6-dichlorobenzyl bromide (0.95mol) obtained in the step a) with 475mL of 2-methyltetrahydrofuran in a constant volume manner to obtain a 2, 6-dichlorobenzyl bromide solution with the concentration of 2 mol/L;
adding 68.4g of magnesium chips (2.85mol, the molar ratio of 2.85mol to 2, 6-dichlorobenzyl bromide is 3: 1) into a reaction container 2 with a condensing device, introducing nitrogen for replacement, adding 50mL of 2-methyltetrahydrofuran and 0.05g of iodine into the reaction container 2, and stirring at the temperature of 65-70 ℃; then, 2, 6-dichlorobenzyl bromide solution with the concentration of 2mol/L is dripped into the reaction container 2 at the dripping speed of 6-7mL/min for Grignard reaction, and after the dripping is finished, the temperature is kept at 65-70 ℃ for continuous stirring for 1h, so that reaction liquid 2 is obtained;
cooling the temperature of the reaction liquid 2 to 20-30 ℃, introducing 426mL of carbon dioxide (2.85mol, and the molar ratio of 2, 6-dichlorobenzyl bromide is 3: 1) into the reaction liquid 2 to perform addition reaction, and keeping the temperature at 20-30 ℃ and continuously stirring for 3 hours to obtain a reaction liquid 3;
filtering the obtained reaction liquid 3 to obtain a filter cake, wherein the main component of the filter cake is magnesium chips; concentrating the obtained filtrate under reduced pressure, and cooling and recovering discharged gas in the process of reducing pressure to obtain 2-methyltetrahydrofuran for recycling; adding 500mL of methanol into the concentrate obtained by decompression concentration, and stirring and dissolving to obtain a reaction solution 4;
dropwise adding 1L of 2mol/L hydrochloric acid aqueous solution into the reaction liquid 4, continuously separating out white solid in the dropwise adding process, performing reduced pressure suction filtration after the dropwise adding is finished, washing the obtained filter cake with deionized water until the washing effluent is neutral, and performing forced air drying at the temperature of 70-80 ℃ for 5-6 hours to obtain 185g of a white solid product 2; the purity was 99.5% from the HPLC chart.
Taking the white solid product 2 for nuclear magnetic resonance detection, wherein the obtained nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (400MHz, dmso) δ 12.60(s,1H),7.44(d, J ═ 8.0Hz,2H),7.29(t, J ═ 8.0Hz,1H),3.87(s,1H), then the target product obtained in step b) the grignard reaction and addition reaction was 2, 6-dichlorophenylacetic acid with a molar yield of 95%.
Compared with the raw material 2, 6-dichlorotoluene, the total yield of the target product 2, 6-dichlorophenylacetic acid is 90%.
Example 2
A process for the preparation of 2, 6-dichlorophenylacetic acid which comprises the steps of example a) wherein 326g of 1, 3-dibromo-5, 5-dimethylhydantoin (1.2 mol: 2, 6-dichlorotoluene in a molar ratio of 1.2: 1) otherwise, the same as example 1, 2, 6-dichlorotoluene and the above brominating reagent were subjected to bromination reaction to obtain 216g of 2, 6-dichlorobenzyl bromide with a molar yield of 90% and a purity of 99.0%.
When different bromination reagents in examples 1 and 2 are used for bromination reaction with 2, 6-dichlorotoluene, the purity of the finally obtained 2, 6-dichlorobenzyl bromide is similar and can meet the requirements of European pharmacopoeia (> 99%), but the yield thereof has large difference, and when N-bromosuccinimide is used as the bromination reagent, the molar yield of the 2, 6-dichlorobenzyl bromide is higher and can reach 95%. This is probably because the succinimide, which is a by-product produced during the bromination reaction of N-bromosuccinimide, has a very weak nucleophilicity, and thus the further reaction of the by-product produced during the reaction with the already produced 2, 6-dichlorobenzyl bromide can be reduced, thereby increasing the yield of 2, 6-dichlorobenzyl bromide.
The examples of the present application are only exemplified by N-bromosuccinimide and 1, 3-dibromo-5, 5-dimethylhydantoin, but do not affect the use of pyridinium hydrobromide in the preparation process of the present application.
Example 3
The preparation method of 2, 6-dichlorophenylacetic acid is the same as the preparation method of the example 1 except that the organic solvent I in the step a) of the example is acetonitrile, and the bromination reaction is carried out on the 2, 6-dichlorotoluene and a bromination reagent in the organic solvent I, so that 218.4g of 2, 6-dichlorobenzyl bromide is finally obtained, the molar yield is 91%, and the purity is 99.0%.
Example 4
The preparation method of 2, 6-dichlorophenylacetic acid is the same as the preparation method of the example 1 except that the organic solvent I in the step a) of the example is trichloromethane, and the bromination reaction is carried out on 2, 6-dichlorotoluene and a bromination reagent in the organic solvent I, so as to obtain 220.8g of 2, 6-dichlorobenzyl bromide, wherein the molar yield is 92% and the purity is 99.0%.
When the organic solvents I are different in step a) of examples 1, 3-4, the purity of the 2, 6-dichlorobenzyl bromide obtained is satisfactory (purity > 99%), but the yields are slightly different. When the organic solvent I is dichloromethane, the yield of the obtained 2, 6-dichlorobenzyl bromide is highest and can reach 95 percent. This is probably because dichloromethane is a weakly polar solvent, which makes the reaction of N-bromosuccinimide with 2, 6-dichlorotoluene more selective, thereby reducing the production of polybrominated by-products and increasing the yield of the brominated product 2, 6-dichlorobenzyl bromide.
The examples of the present application are illustrated with only dichloromethane, acetonitrile and chloroform, but do not affect the use of dichloroethane, carbon tetrachloride and chloroform in the process of the present application.
Example 5
A process for the preparation of 2, 6-dichlorophenylacetic acid except that in step a) of this example, the brominating agent N-bromosuccinimide was used in an amount of 195.8g (1.1mol, molar ratio to 2, 6-dichlorotoluene was 1.1: 1) otherwise, as in example 1, the bromination reaction of 2, 6-dichlorotoluene and a bromination reagent gave 218.4g of 2, 6-dichlorobenzyl bromide in a molar yield of 91% and a purity of 99.0%.
Example 6
A process for the preparation of 2, 6-dichlorophenylacetic acid, except that in step a) of this example the brominating agent N-bromosuccinimide was used in an amount of 270.1g (1.5mol, molar ratio to 2, 6-dichlorotoluene 1.5: 1) otherwise, the same procedure as in example 1 was repeated, except that 2, 6-dichlorotoluene and a brominating reagent were subjected to bromination reaction to obtain 235.2g of 2, 6-dichlorobenzyl bromide, which had a molar yield of 98% and a purity of 98.0%.
Example 7
A process for the preparation of 2, 6-dichlorophenylacetic acid, except that in step a) of this example the brominating agent N-bromosuccinimide was used in an amount of 284.8g (1.6mol, molar ratio to 2, 6-dichlorotoluene 1.6: 1) otherwise, the same procedure as in example 1 was repeated, and 242.4g of 2, 6-dichlorobenzyl bromide was finally obtained by bromination of 2, 6-dichlorotoluene with a brominating agent in a molar yield of 101% and a purity of 96.0%.
When the molar ratio of the 2, 6-dichlorotoluene to the brominating agent is different in examples 1, 5-7, the yield and purity of the obtained 2, 6-dichlorobenzyl bromide are greatly different, and the following table specifically shows that:
as can be seen from the above table, when the molar ratio of the brominating agent to 2, 6-dichlorotoluene is different, the yield and purity of the finally obtained 2, 6-dichlorobenzyl bromide are different, when the molar ratio of the brominating agent to 2, 6-dichlorotoluene is 1.6: when 1, the molar yield exceeds the theoretical value because the molecular weight of the dibromo-impurity produced is larger than that of the target product.
When the molar ratio of the brominating agent to the 2, 6-dichlorotoluene is 1.1-1.5: 1, the molar yield of 2, 6-dichlorobenzyl bromide gradually increases, but the purity thereof increases and then decreases, because 2, 6-dichlorotoluene cannot be completely reacted when the amount of the brominating agent is too small; when the amount of the brominating agent is excessive, the generated 2, 6-dichlorobenzyl bromide reacts with the excessive brominating agent further to generate dibromo impurities with larger molecular weight; wherein when the molar ratio of the brominating agent to the 2, 6-dichlorotoluene is 1.2: 1, the purity and the yield of the obtained 2, 6-dichlorobenzyl bromide reach the highest values, the molar yield can reach 95 percent, and the purity can reach 99.5 percent.
Example 8
A process for producing 2, 6-dichlorophenylacetic acid, which was the same as in example 1 except that 4mol/L of an aqueous hydrochloric acid solution was added dropwise to the reaction mixture 4 in the step b) of this example, and the amount of the aqueous hydrochloric acid solution was changed to 1L, was changed to 185.2g, and the process gave 95.1% molar yield and 99.5% purity.
It can be seen from examples 1 and 8 that, when the concentration of the aqueous hydrochloric acid solution is 2-4mol/L, the aqueous hydrochloric acid solution is added dropwise to adjust the pH of the reaction solution 4 to be less than 2 until the target product 2, 6-dichlorophenylacetic acid is completely precipitated, and the purity of the obtained 2, 6-dichlorophenylacetic acid can reach 99.5%, but the yield is almost the same.
Example 9
A method for producing 2, 6-dichlorophenylacetic acid was carried out in the same manner as in example 1 except that in step b) of this example, 2-methyltetrahydrofuran was mixed with 2, 6-dichlorobenzyl bromide obtained in step a) to give 2, 6-dichlorobenzyl bromide at a concentration of 1mol/L, and the mixture was subjected to Grignard reaction and addition reaction to give 183g of 2, 6-dichlorophenylacetic acid at a molar yield of 94% and a purity of 99.5%.
Example 10
A process for producing 2, 6-dichlorophenylacetic acid which was substantially the same as that used in example 1 except that 2-methyltetrahydrofuran was mixed with 2, 6-dichlorobenzyl bromide obtained in step b) in the present example to give a concentration of 2, 6-dichlorobenzyl bromide of 1.5mol/L, was further subjected to Grignard reaction and addition reaction to give 184g of 2, 6-dichlorophenylacetic acid in a molar yield of 94.5% and a purity of 99.5%.
Example 11
A process for producing 2, 6-dichlorophenylacetic acid, which was the same as in example 1 except that in step b) of this example, 2-methyltetrahydrofuran was mixed with 2, 6-dichlorobenzyl bromide obtained in step a) to give 2, 6-dichlorobenzyl bromide in a concentration of 2.5mol/L, was further subjected to Grignard reaction and addition reaction to give 177.2g of 2, 6-dichlorophenylacetic acid in a molar yield of 91% and a purity of 99.5%.
Example 12
A method for producing 2, 6-dichlorophenylacetic acid was carried out in the same manner as in example 1 except that in step b) of this example, 2-methyltetrahydrofuran was mixed with 2, 6-dichlorobenzyl bromide obtained in step a) to give 2, 6-dichlorobenzyl bromide in a concentration of 3mol/L, and further subjected to Grignard reaction and addition reaction to give 167.5g of 2, 6-dichlorophenylacetic acid in a molar yield of 86% and a purity of 99.5%.
When the concentrations of 2, 6-dichlorobenzyl bromide are different in step b) of examples 1, 9-12, the purity of the finally obtained 2, 6-dichlorophenylacetic acid meets the requirements of the european pharmacopoeia (purity > 99%), but the yields are quite different, as specified in the following table:
as can be seen from the table above, the different concentrations of 2, 6-dichlorobenzyl bromide in the Grignard reaction in the step b) have a great influence on the yield of 2, 6-dichlorophenylacetic acid, and when the concentration of 2, 6-dichlorobenzyl bromide is 1.0-2.5mol/L, the molar yield of the target product, 2, 6-dichlorophenylacetic acid, can reach 91-95%; wherein when the concentration of the 2, 6-dichlorobenzyl bromide is 2.0mol/L, the molar yield of the 2, 6-dichlorophenylacetic acid is the highest and can reach 95 percent. The reason for this analysis may be that the concentration of 2, 6-dichlorobenzyl bromide mainly affects the proportion of coupling impurities generated in the reaction system, and when the concentration of 2, 6-dichlorobenzyl bromide is 2.0mol/L, the coupling impurities generated in the reaction system are the least, and the yield of the finally obtained 2, 6-dichlorophenylacetic acid is the highest.
Example 13
The preparation method of 2, 6-dichlorophenylacetic acid was performed in the same manner as in example 1 except that tetrahydrofuran was used as the organic solvent II in the step b) of this example, and subjected to Grignard reaction and addition reaction to obtain 146g of 2, 6-dichlorophenylacetic acid in a molar yield of 75% and a purity of 99.5%.
Example 14
A process for producing 2, 6-dichlorophenylacetic acid in the same manner as in example 1 except that in step b) of this example, the organic solvent II was ether, followed by Grignard reaction and addition reaction, gave 107.1g of 2, 6-dichlorophenylacetic acid in a molar yield of 55% and a purity of 99.5%.
Example 15
The preparation method of 2, 6-dichlorophenylacetic acid was carried out in the same manner as in example 1 except that the organic solvent II in the step b) of this example was methyl t-butyl ether, and subjected to Grignard reaction and addition reaction to obtain 68.2g of 2, 6-dichlorophenylacetic acid in a molar yield of 35% and a purity of 99.5%.
Example 16
A process for producing 2, 6-dichlorophenylacetic acid in the same manner as in example 1 except that n-heptane was used as the organic solvent II in the step b) in the present example, whereby 70.1g of 2, 6-dichlorophenylacetic acid was obtained in a molar yield of 36% and a purity of 99.5% through the Grignard reaction and addition reaction.
When the organic solvent II is different in step b) of examples 1, 13-16, the purity of the finally obtained 2, 6-dichlorophenylacetic acid is satisfactory (purity > 99%), but the yields are quite different, as shown in the following table:
as can be seen from the above table, when the organic solvent II is different in step b), the yield of the finally obtained 2, 6-dichlorophenylacetic acid has a large difference. Wherein, when the organic solvent II is 2-methyltetrahydrofuran, the molar yield of the 2, 6-dichlorophenylacetic acid is the highest and can reach 95 percent. The reason for this is probably because other organic solvents II generate coupling impurities with 2, 6-dichlorobenzyl bromide and 2, 6-dichlorophenylacetic acid in the reaction system of the Grignard reaction, thereby reducing the yield of 2, 6-dichlorophenylacetic acid.
Example 17
A process for the preparation of 2, 6-dichlorophenylacetic acid, which comprises the steps of, except that in step b) of this example, magnesium chloride chips are used in a molar ratio of 1: the same procedures used in example 1 were repeated except for using the same solvent as in example 1 to give 167.5g of 2, 6-dichlorophenylacetic acid in a molar yield of 86% and a purity of 99.5% by Grignard reaction and addition reaction.
Example 18
A process for the preparation of 2, 6-dichlorophenylacetic acid, except that in step b) of this example, magnesium turnings were used in a molar ratio of 2, 6-dichlorobenzyl bromide from step a): except for 1, 179.2g of 2, 6-dichlorophenylacetic acid was finally obtained in the same manner as in example 1 through Grignard reaction and addition reaction, and the molar yield was 92% and the purity was 99.5%.
Example 19
A process for the preparation of 2, 6-dichlorophenylacetic acid, which comprises the steps of, except that in step b) of this example, magnesium chloride chips are used in a molar ratio of 4: otherwise, 185.2g of 2, 6-dichlorophenylacetic acid was finally obtained in the same manner as in example 1 except that the reaction mixture was subjected to the Grignard reaction and addition reaction, and the molar yield thereof was 95.1% and the purity thereof was 99.5%.
Example 20
A process for the preparation of 2, 6-dichlorophenylacetic acid, which comprises the steps of, except that in step b) of this example, magnesium chloride chips are used in a molar ratio of 6: otherwise, 185.1g of 2, 6-dichlorophenylacetic acid was finally obtained in the same manner as in example 1 except that the reaction mixture was subjected to the Grignard reaction and addition reaction, and the molar yield thereof was 95% and the purity thereof was 99.5%.
When the amount of magnesium chips used in step b) of examples 1, 17-20 is different from the molar ratio of 2, 6-dichlorobenzyl bromide obtained in step a), the purity of the finally obtained 2, 6-dichlorophenylacetic acid is satisfactory (purity > 99.5%), but the yield is quite different, as shown in the following table:
as shown in the table above, when the amount of magnesium chips used in step b) is (2-6) in molar ratio to the 2, 6-dichlorobenzyl bromide obtained in step a): 1, the molar yield of the target product 2, 6-dichlorophenylacetic acid can reach 92-95%; wherein, when the molar ratio of the magnesium chips used in the step b) to the 2, 6-dichlorobenzyl bromide obtained in the step a) is 3: 1, the final obtained 2, 6-dichlorophenylacetic acid has the highest molar yield which can reach 95 percent. When the molar ratio of the magnesium chips to the 2, 6-dichlorobenzyl bromide obtained in step a) is less than 3: 1, the yield of the 2, 6-dichlorophenylacetic acid is increased along with the increase of the dosage of the magnesium chips; when the molar ratio of the magnesium chips to the 2, 6-dichlorobenzyl bromide obtained in step a) is higher than 3: at 1 hour, the yield of the target product 2, 6-dichlorophenylacetic acid cannot be obviously improved by increasing the dosage of the magnesium chips. Thus, the amount of magnesium turnings used in step b) is chosen so that the molar ratio of the magnesium turnings used to the 2, 6-dichlorobenzyl bromide obtained in step a) is 3: 1 can obtain the best yield and simultaneously save the consumption of reactants to save the cost.
As can be seen from the purity data of the 2, 6-dichlorophenylacetic acid as the target product obtained by the reactions of examples 9 to 20, the purity of the obtained 2, 6-dichlorophenylacetic acid can reach 99.5% no matter how the concentration of 2, 6-dichlorobenzyl bromide, the amount of the organic solvent II and the amount of magnesium chips are changed during the reaction of the Grignard reaction and the addition reaction, as long as the crystallization reaction conditions are such that the pH of the solution is less than 2 by adding 2 to 4mol/L of the hydrochloric acid aqueous solution dropwise. It is thus shown that in the process for the preparation of 2, 6-dichlorophenylacetic acid according to the present application, the above-mentioned crystallization conditions are one of the main conditions affecting the purity of 2, 6-dichlorophenylacetic acid.
In summary, the method for preparing 2, 6-dichlorophenylacetic acid in the present application uses 2, 6-dichlorotoluene as an initial material, and develops a brand new method for preparing 2, 6-dichlorophenylacetic acid: namely, the 2, 6-dichlorotoluene is subjected to one-pot reaction of bromination reaction, Grignard reaction and addition reaction in sequence in one pot, and the total two-step reaction is adopted to prepare the 2, 6-dichlorophenylacetic acid. 2, 6-dichlorotoluene is selected as an initial raw material, and magnesium chips and carbon dioxide are selected to perform a Grignard reaction and an addition reaction respectively, and the raw material is simple and easy to obtain and has low price, so that the preparation method of the application has low cost. Furthermore, the reaction process conditions of the bromination reaction, the Grignard reaction and the addition reaction are mild, and the means of influencing the operation safety, such as high temperature and/or high pressure conditions or the participation of toxic substances in the reaction and the like, are not needed, so that the safety of the reaction process is greatly improved; the Grignard reaction and the addition reaction adopt a one-pot method, so that the reaction steps of the preparation process are less, and the further industrial application of the preparation process is facilitated. Therefore, the preparation method has the advantages of low cost, high operation safety and few reaction steps, and can be further applied to industrial production.
Furthermore, in the preparation method of 2, 6-dichlorophenylacetic acid, a bromination reagent selected in the bromination reaction is subjected to substitution reaction with benzylic hydrogen of 2, 6-dichlorotoluene in an organic solvent I, so that the method has high selectivity, and the yield and the purity of the bromination product 2, 6-dichlorobenzyl bromide are improved; the use amount of the selected brominating agent and the organic solvent I are matched, and a sodium sulfite aqueous solution with the mass percentage concentration of 10% is adopted as an extracting agent to react with the redundant brominating agent, so that the yield and the purity of the final product of the brominating reaction, namely the 2, 6-dichlorobenzyl bromide, can be remarkably improved, and the 2, 6-dichlorobenzyl bromide can obtain higher yield on the premise that the purity is more than 99%, and the highest yield can reach 95%.
Further, according to the preparation method of 2, 6-dichlorophenylacetic acid, when the Grignard reagent is prepared, the selected organic solvent II and the reaction condition for diluting the 2, 6-dichlorobenzyl bromide to a specific concentration can both reduce the generation of coupling impurities and the dissolution enrichment effect, so that the purity of the target product 2, 6-dichlorophenylacetic acid is improved; furthermore, the proper magnesium chip dosage can reduce the cost of the Grignard reaction while ensuring the complete reaction; furthermore, methanol and 2-4mol/L hydrochloric acid aqueous solution are adopted to carry out crystallization reaction on the product after the Grignard reaction and the addition reaction, so that 2, 6-dichlorophenylacetic acid can be effectively collected, the reaction condition of the crystallization reaction is obviously improved, the purity of the 2, 6-dichlorophenylacetic acid is improved, the yield of the 2, 6-dichlorophenylacetic acid can reach 95 percent at most, and the purity can reach 99.5 percent.
According to the preparation method of the 2, 6-dichlorophenylacetic acid, the design of the bromination reaction, the Grignard reaction and the addition reaction and the selection and the dosage of each reactant are combined, so that the total yield and the purity of the target product 2, 6-dichlorophenylacetic acid are remarkably improved, and the maximum total yield of the target product 2, 6-dichlorophenylacetic acid can reach 90% compared with the raw material 2, 6-dichlorotoluene.
In summary, the preparation method has low cost, high reaction safety, few reaction steps and high yield and purity of the target product, so that the preparation method has a high value of industrial application.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. The preparation method of 2, 6-dichlorophenylacetic acid is characterized by comprising the following steps:
a) bromination reaction
Mixing 2, 6-dichlorotoluene with a bromination reagent and an organic solvent I, and then carrying out bromination reaction at the temperature of 15-80 ℃ to obtain a reaction solution 1; extracting the obtained reaction solution 1, and concentrating an organic phase to obtain 2, 6-dichlorobenzyl bromide;
b) grignard reactions and addition reactions
Diluting the 2, 6-dichlorobenzyl bromide obtained in the step a) by using an organic solvent II, and dropwise adding the diluted 2, 6-dichlorobenzyl bromide into magnesium chips at the temperature of 65-70 ℃ to perform a Grignard reaction to obtain a reaction solution 2;
cooling the obtained reaction liquid 2 to 20-30 ℃, and introducing excessive carbon dioxide for addition reaction to obtain a reaction liquid 3;
and filtering the obtained reaction solution 3 to obtain filtrate, and carrying out crystallization reaction on the filtrate to obtain the 2, 6-dichlorophenylacetic acid.
2. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 1, wherein the brominating agent is one or more of N-bromosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin and pyridinium hydrogen bromide;
the organic solvent I is one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, acetonitrile and tetrahydrofuran.
3. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 2, wherein said brominating agent is N-bromosuccinimide;
the organic solvent I is dichloromethane.
4. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 3, wherein the brominating agent is used in an amount of 2, 6-dichlorotoluene: the mol ratio of the brominating agent is 1: 1.1-1.5;
the dosage of the organic solvent I is as follows according to 2, 6-dichlorotoluene: 1kg of organic solvent I: 3L.
5. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 4, wherein the brominating agent is used in an amount of 2, 6-dichlorotoluene: the mol ratio of the brominating agent is 1: 1.2.
6. the method for preparing 2, 6-dichlorophenylacetic acid according to claim 5, wherein an extracting agent in the extraction process of the reaction solution 1 is a sodium sulfite aqueous solution with the mass percent concentration of 10%; the molar amount of the sodium sulfite aqueous solution with the mass percentage concentration of 10% is the same as that of the excessive brominating reagent, and the molar amount of the excessive brominating reagent is the theoretical residual amount of the brominating reagent after the brominating reaction is finished.
7. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 6, wherein the crystallization reaction in the grignard reaction and the addition reaction in the step b) is as follows:
filtering the obtained reaction liquid 3 to obtain filtrate, concentrating under reduced pressure, and adding methanol to dissolve to obtain reaction liquid 4; and then dropwise adding 2-4mol/L hydrochloric acid aqueous solution into the reaction solution 4, adjusting the pH of the reaction solution 4 to be less than 2, performing crystallization reaction, and after dropwise adding is finished, performing pressure suction filtration to obtain 2, 6-dichlorophenylacetic acid.
8. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 7, wherein the concentration of the aqueous hydrochloric acid solution is 2mol/L, and the amount of the 2mol/L aqueous hydrochloric acid solution is calculated according to the ratio of the aqueous hydrochloric acid solution: the volume ratio of methanol is 2: 1.
9. the method for preparing 2, 6-dichlorophenylacetic acid according to claim 8, wherein in the step b) of the grignard reaction and the addition reaction, the 2, 6-dichlorobenzyl bromide obtained in the step a) is diluted to 1.0 to 2.5mol/L with the organic solvent II;
the organic solvent II is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether and methyl tert-butyl ether;
the dosage of the magnesium chips is as follows according to 2, 6-dichlorobenzyl bromide: the molar ratio of the magnesium chips is 1: (2-6).
10. The method for preparing 2, 6-dichlorophenylacetic acid according to claim 9, wherein in the step b) of the grignard reaction and the addition reaction, the 2, 6-dichlorobenzyl bromide obtained in the step a) is diluted to 2.0mol/L with the organic solvent II;
the organic solvent II is 2-methyltetrahydrofuran;
the dosage of the magnesium chips is as follows according to 2, 6-dichlorobenzyl bromide: the molar ratio of the magnesium chips is 1: 3.
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| CN117720409A (en) * | 2023-12-28 | 2024-03-19 | 山东国邦药业有限公司 | Synthesis method of difluoroacetic acid |
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