CN113024390B - Synthesis method of 3',5' -dichloro-2, 2-trifluoro acetophenone derivative - Google Patents
Synthesis method of 3',5' -dichloro-2, 2-trifluoro acetophenone derivative Download PDFInfo
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- CN113024390B CN113024390B CN202110198933.6A CN202110198933A CN113024390B CN 113024390 B CN113024390 B CN 113024390B CN 202110198933 A CN202110198933 A CN 202110198933A CN 113024390 B CN113024390 B CN 113024390B
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- 238000001308 synthesis method Methods 0.000 title claims description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 12
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- -1 trifluoroacetyl compound Chemical class 0.000 claims abstract description 6
- 238000010306 acid treatment Methods 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- 239000002904 solvent Substances 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 13
- WXBWKMLIVXELSF-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-dimethylacetamide Chemical compound CN(C)C(=O)C(F)(F)F WXBWKMLIVXELSF-UHFFFAOYSA-N 0.000 claims description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- 239000003999 initiator Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- CODXZFSZJFCVBE-UHFFFAOYSA-N n,n-diethyl-2,2,2-trifluoroacetamide Chemical compound CCN(CC)C(=O)C(F)(F)F CODXZFSZJFCVBE-UHFFFAOYSA-N 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 7
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical group BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 5
- 230000020477 pH reduction Effects 0.000 claims description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000009776 industrial production Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012467 final product Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- NPQBZKNXJZARBJ-UHFFFAOYSA-N 4-bromo-2,6-dichloroaniline Chemical compound NC1=C(Cl)C=C(Br)C=C1Cl NPQBZKNXJZARBJ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MMJSIYGLDQNUTH-UHFFFAOYSA-N 5-bromo-1,3-dichloro-2-fluorobenzene Chemical compound FC1=C(Cl)C=C(Br)C=C1Cl MMJSIYGLDQNUTH-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- DZHFFMWJXJBBRG-UHFFFAOYSA-N 1-bromo-3,5-dichlorobenzene Chemical compound ClC1=CC(Cl)=CC(Br)=C1 DZHFFMWJXJBBRG-UHFFFAOYSA-N 0.000 description 1
- VZUMVBQMJFFYRM-UHFFFAOYSA-N 5-bromo-1,2,3-trichlorobenzene Chemical compound ClC1=CC(Br)=CC(Cl)=C1Cl VZUMVBQMJFFYRM-UHFFFAOYSA-N 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- CPNKGYIQPKUCCM-UHFFFAOYSA-N N-ethyl-N-(2,2,2-trifluoroethyl)acetamide Chemical compound CCN(C(C)=O)CC(F)(F)F CPNKGYIQPKUCCM-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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 System
- C07F3/02—Magnesium compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The application relates to the technical field of chemical pharmacy, in particular to a method for synthesizing 3',5' -dichloro-2, 2-trifluoro acetophenone derivatives, which specifically comprises the following steps: s1, preparing a Grignard reagent from a 1-bromo-3, 5-dichloro-4-substituted compound by using the Grignard reagent; s2, reacting a Grignard reagent with a trifluoroacetyl compound, and then carrying out acid treatment to obtain the 3',5' -dichloro-2, 2-trifluoroacetophenone derivative. The technical scheme adopted in the application has mild reaction conditions, easily obtained raw materials and higher yield, is beneficial to saving the production cost of enterprises and is suitable for large-scale production.
Description
Technical Field
The application relates to the technical field of chemical pharmacy, in particular to a method for synthesizing 3',5' -dichloro-2, 2-trifluoro acetophenone derivatives.
Background
The 3',5' -dichloro-2, 2-trifluoro acetophenone derivative is an important medical intermediate, and is substituted at the 4' position, so that the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative has different properties, and has important significance for regulating pharmacological properties and subsequent further modification and development.
3',5' -dichloro-2, 2-trifluoro acetophenone derivatives are generally prepared by taking 3, 5-dichloro bromobenzene as a raw material, extracting bromine atoms through strong alkali under the deep cooling condition of minus 78-70 ℃, then reacting with an organic fluorine reagent, and replacing the bromine atoms with trifluoro acetyl groups.
In the reaction process, strong alkali is needed to participate in the reaction, the whole reaction is needed to be carried out under a cryogenic condition, the energy consumption is high, the requirement on equipment is high when the large-scale production is carried out, the economic effect is poor, and the method is not suitable for industrial production.
Disclosure of Invention
In order to reduce the industrial production cost of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative, the application provides a synthesis method of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative.
The application provides a synthesis method of 3',5' -dichloro-2, 2-trifluoro acetophenone derivatives, which adopts the following technical scheme:
the synthesis method of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative comprises the following steps:
s1, preparing a compound I into a compound II through a Grignard reagent;
s2, reacting the compound II with the compound III, and then carrying out acid treatment to obtain a 3',5' -dichloro-2, 2-trifluoro acetophenone derivative;
compound I is shown below:
in the compound I, R1 is NH 2 Any one of Cl and F;
compound II is shown below:
compound III is shown below:
wherein R is 2 Is Na (Na) + 、Zn 2+ 、Mg 2+ 、Cu 2+ 、Li + 、K + 、Ca 2+ 、Ni 2+ One of them, and n is R 2 The number of positive charges carried; r is R 3 Is Cl,Br, F, dimethylamino, diethylamino, piperidinyl, morpholinyl, or tetrahydropyrrole.
In the technical scheme, the Grignard reagent is formed through the Grignard reaction, and then trifluoroacetamide, trifluoroacetyl chloride or trifluoroacetate is utilized to carry out the replacement reaction with the Grignard reagent, so that the 3',5' -dichloro-2, 2-trifluoroacetophenone derivative substituted at the 4' -position is prepared with high selectivity. In the process, strong alkali is not needed in the whole process, the reaction condition is mild, the reaction can be completed without a cryogenic condition, the post-treatment process is easy, most of redundant impurities have good solubility in water, and the organic phase has poor solubility, so that raw materials and impurities can be separated easily, and the production cost can be reduced well. In addition, R1 is one of amino, chlorine or fluorine, has good stability, can not participate in the reaction basically in the reaction process, has fewer impurities in the final product, and can be successfully developed after further modification.
In conclusion, the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative adopting the technical scheme has higher yield, lower cost and milder reaction condition, has good economic effect and is suitable for large-scale production.
Optionally, in step S1, magnesium metal is selected as the grignard reagent, and step S1 is specifically as follows:
s1-1, dispersing metal magnesium in a solvent I to obtain a mixed system I;
s1-2, weighing a compound I, and dissolving the compound I in a solvent II to obtain a mixed system II;
s1-3, maintaining the temperature of the mixed system I at 0-100 ℃, adding an initiator into the mixed system, then dropwise adding the mixed system II within 30-60 min after heat preservation, and cooling the reaction system to below 15 ℃ after the dropwise adding is completed and the two are fully reacted to obtain a mixed system III, wherein the mixed system III contains a compound II;
wherein, the solvent I and the solvent II are independent of each other and are one of tetrahydrofuran, methyl tertiary butyl ether, petroleum ether, benzene, toluene, pentane, hexane and heptane or a homogeneous system formed by any of tetrahydrofuran, methyl tertiary butyl ether, petroleum ether, benzene, toluene, pentane, hexane and heptane; and the solvent I and the solvent II can form a miscible homogeneous system in any proportion; the total weight of the solvent I and the solvent II is 3-20 times of the weight of the compound II;
the initiator is 1, 2-dibromoethane or iodine.
In the technical scheme, magnesium and the solvent I are mixed to form a mixed system I, and then the mixed system II formed by dissolving the compound I in the solvent II is dripped into the mixed system I, so that on one hand, the compound I can fully react in the environment of high-concentration magnesium in the process, the loss of the compound I is reduced, the occurrence of side reactions is inhibited, and meanwhile, the occurrence intensity of the reaction is reduced, the temperature is easier to control, and the yield is further improved.
Optionally, the solvent I and the solvent II are tetrahydrofuran, and the total weight of the solvent I and the solvent II is 3-10 times of the weight of the compound I.
Tetrahydrofuran is selected as a solvent, so that the tetrahydrofuran has wide sources and low cost, has better solubility for various materials, reduces the use amount of the solvent and further saves the production cost.
Alternatively, in step S1-3, the reaction temperature is 20-60 ℃.
The reaction temperature is controlled within the range of 20-60 ℃, the reaction efficiency is higher, side reactions are not easy to occur, and the yield and purity of the final product are higher, thus having better industrial production and application prospects. In addition, in the reaction, the reaction temperature is easy to control in practice, the reaction is carried out at room temperature, the temperature generated after the exothermic reaction can basically fall in the range of 20-60 ℃, and the temperature control is convenient.
Optionally, step S2 is specifically as follows:
s2-1, uniformly dropwise adding the compound III into the mixed system III obtained in the step S1-3 within 1-2 h at the temperature of minus 20-30 ℃, and fully reacting after the dropwise adding is finished, so as to obtain a mixed system IV;
s2-2, adding acid I into the mixed system IV for acidification, and then further treating to remove a solvent to obtain 3',5' -dichloro-4 ' -R1-2, 2-trifluoro acetophenone;
wherein the acid I is any one of sulfuric acid, hydrochloric acid and phosphoric acid.
In the technical scheme, the mixed system III can be directly subjected to the next reaction without separation, so that the production process is simplified. In the step S2-1, the occurrence of side reaction is restrained through lower reaction temperature, but the deep cooling condition is not needed, thereby being beneficial to further reducing the industrial production cost and having good application prospect in the large-scale industrial production process.
Optionally, the acid I is hydrochloric acid with a mass fraction of 5-10%.
The dilute hydrochloric acid acidification can realize the rapid quenching process of the reaction and reduce the occurrence of side reactions, so that the final purity is improved, and the chloride generated after quenching is easy to dissolve in water and can be directly removed by extraction, thereby simplifying the post-treatment procedure. Meanwhile, the price of hydrochloric acid is lower, the corrosiveness to equipment is also lower, the safety is better, the industrial production cost is further reduced, and the economic effect is improved.
Alternatively, compound III is trifluoroacetyl dimethylamine or trifluoroacetyl diethylamine.
The reaction is carried out within the range of 10-30 ℃, the reaction rate is faster, the temperature is easy to control, the production cost is further reduced, the yield of the final product is improved, and better economic effect is obtained.
Alternatively, the amount of the trifluoroacetyl group-containing substance contained in the added compound III is 1.05 to 12.2 times the amount of the compound I.
In the technical scheme, trifluoroacetamide is selected as a trifluoroacetyl reagent. The trifluoroacetyl dimethylamine and the trifluoroacetyl diethylamine have better solubility in an organic phase, and the products of the trifluoroacetyl dimethylamine and the trifluoroacetyl diethylamine have better water solubility after acidification, so that the main products and the byproducts are easier to separate after the reaction is finished, and the purity of the target products is improved. Meanwhile, compared with trifluoroacetyl halide, the trifluoroacetyl halide has the advantages of mild reaction, difficult occurrence of temperature runaway phenomenon and less corrosiveness to equipment. Therefore, the trifluoro acetyl dimethylamine or trifluoro acetyl diethylamine is used as the trifluoro acetyl reagent, which is beneficial to reducing the production cost of enterprises, further improving the economic effect of the enterprises and having better application prospect.
Alternatively, 9
The compound III is excessive during addition, so that the compound II can fully react, the residue of the compound II is reduced, on the one hand, in the acidification process, the added acid is not easy to react with the compound II, the system is unstable, the residue of the compound II or the compound I in the system is reduced, and the purity of a target product finally prepared is improved.
In summary, the technical scheme of the application comprises at least one of the following beneficial effects:
1. in the application, the compound I and the Grignard reagent react to generate the compound II, and then the compound II and the compound III react to generate the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative, so that the whole reaction condition is mild, the raw materials are simple and easy to obtain, the post-treatment can be easily carried out, the production cost is saved for enterprises, the economic effect is good, and the method is suitable for large-scale production.
2. In the step S1, the intensity of the reaction is reduced by respectively configuring the mixed system I and the mixed system II, the compound I can fully react, the yield is improved, the temperature is easier to control, and the occurrence of side reaction is reduced.
3. In the step S2, the mixed system obtained in the step S1 is directly subjected to continuous reaction at a lower temperature, so that the yield is further improved, and the industrial production cost is reduced.
Detailed Description
The present application will be described in further detail with reference to examples.
Example 1
The synthesis method of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative is used for preparing 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone, and the specific preparation process is as follows:
s1, preparing a compound I into a compound II through a Grignard reagent;
s2, reacting the compound II with the compound III, and then carrying out acid treatment to obtain the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative.
In example 1, compounds I to 3 are shown below.
Wherein, S1 specifically includes the following steps:
s1-1, weighing 5.35g of magnesium chips (0.22 mol), adding 120mL of tetrahydrofuran (solvent I) into a reaction bottle, and uniformly stirring at room temperature to obtain a mixed system I;
s1-2, weighing 48.2g (0.2 mol) of 3, 5-dichloro-4-aminobromobenzene (compound I), dissolving with 100mL of tetrahydrofuran (solvent II) to obtain a mixed system II, and placing the mixed system II in a separating funnel for later use;
s1-3, heating the mixed system I in the reaction bottle to 20 ℃, adding 1mL of 1, 2-dibromoethane as an initiator, uniformly dropwise adding the mixed system II into the mixed system I within 60min, preserving heat at 20 ℃ after dropwise adding, and continuously preserving heat for 5h to obtain a mixed system III.
The step S2 specifically comprises the following steps:
s2-1, controlling the temperature of the mixed system III obtained in the step S1-3 to 20 ℃, uniformly dropwise adding 46.6g of trifluoroacetyl dimethylamine (0.33 mol) into the system within 20min, and continuously stirring for 1h after the dropwise adding is finished to obtain a mixed system IV;
s2-2, adding 100mL of hydrochloric acid (acid I) with mass fraction of 5% into the mixed system IV, preserving heat, standing, separating liquid, retaining an organic phase, evaporating tetrahydrofuran in the organic phase, rectifying the product to obtain clear and transparent liquid, namely 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone, and measuring nuclear magnetic resonance hydrogen spectrum of the final product in deuterated chloroform to obtain specific data as follows: 1H NMR(400MHz,CDC1 3 ):7.95(s,2H),5.23(bs,2H)ppm。
Examples 2 to 14
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in step S2, the selection and addition of compound III are shown in Table I.
Meanwhile, in examples 1 to 14, the yields and purities of the aimed products were as shown in Table 1,
table 1: examples 1 to 14 give yields and purities of 3',5' -dichloro-4 ' -amino-2, 2-trifluoroacetophenone
According to the experimental data, the 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone is prepared by adopting the technical scheme, has higher yield, can reach higher purity, and has the purity of more than 98 percent. The compound III is replaced, and the trifluoroacetyl dimethylamine and the trifluoroacetyl diethylamine are selected, so that the final yield is higher and the purity is better.
It can be seen from examples 9 to 14 that when the ratio of the amount of trifluoroacetyl dimethylamine to the amount of the compound I is 1.04 to 12.2:1, the reaction yield is high and the purity of the final product is high. When the amount of trifluoroacetyl dimethylamine added is too large, the subsequent separation of the product is affected, so that the impurity content is increased, and when the ratio of the amount of trifluoroacetyl dimethylamine to the amount of the compound I is 1:1, the yield is significantly reduced.
Further, the following examples were obtained by adjusting some of the parameters in step S1 and step S2.
Example 15
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative was different from example 1 in that in step S1-1, the amount of tetrahydrofuran added was 240mL, and in step S1-2, the amount of tetrahydrofuran added was 300mL.
Example 16
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative was different from example 1 in that in step S1-1, the amount of tetrahydrofuran added was 75mL, and in step S1-2, the amount of tetrahydrofuran added was 88mL.
Example 17
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative was different from example 1 in that in step S1-1, the amount of tetrahydrofuran added was 480mL, and in step S1-2, the amount of tetrahydrofuran added was 600mL.
Example 18
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in both step S1-1 and step S1-2, solvent I and solvent II are replaced by equal volumes of methyl tert-butyl ether.
Example 19
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in both step S1-1 and step S1-2, solvent I and solvent II are replaced by equal volumes of n-heptane.
Example 20
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in step S1-1 and step S1-2, solvent I is replaced with an equal volume of benzene and solvent II is replaced with an equal volume of toluene.
Example 21
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in step S1-1 and step S1-2, solvent I is replaced with an equal volume of petroleum ether and solvent II is replaced with an equal volume of hexane.
Example 22
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in step S1-3, the dropwise addition time of the mixed system II was 30min.
Examples 23 to 26
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative is different from example 1 in that in step S1-3, the reaction temperature is 0℃at 40℃at 60℃at 100℃respectively.
Example 27
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that the initiator is 0.5g elemental iodine.
Example 28
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that step S1 is specifically as follows:
s1, weighing 48.2g (0.2 mol) of 3, 5-dichloro-4-aminobromobenzene (compound I), dissolving with 200mL of tetrahydrofuran (solvent II), adding 5.35g of magnesium chips into the system at room temperature, adding 1mL of 1, 2-dibromoethane as an initiator, and then carrying out heat preservation reaction for 5h to obtain a mixed system III.
For examples 15 to 28, the yields and purities of the target products are shown in Table 2.
Table 2: examples 15 to 28 give yields and purities of 3',5' -dichloro-4 ' -amino-2, 2-trifluoroacetophenone
| Example sequence number | Yield rate | Purity of |
| Example 15 | 89.9％ | 99.4％ |
| Example 16 | 89.2％ | 99.2％ |
| Example 17 | 87.7％ | 99.1％ |
| Example 18 | 86.3％ | 99.5％ |
| Example 19 | 88.4％ | 98.5％ |
| Example 20 | 87.8％ | 99.0％ |
| Example 21 | 88.1％ | 99.3％ |
| Example 22 | 89.7％ | 99.2％ |
| Example 23 | 86.5％ | 99.4％ |
| Example 24 | 89.9％ | 99.1％ |
| Example 25 | 89.5％ | 99.3％ |
| Example 26 | 88.8％ | 98.0％ |
| Example 27 | 85.0％ | 99.1％ |
| Example 28 | 81.9％ | 98.7％ |
From the above experimental data, it is found that the adjustment of the solvent and the reaction temperature in step S1 has a certain influence on the yield and purity of the reaction. The tetrahydrofuran is selected for reaction, so that the yield is higher, and the tetrahydrofuran has certain hydrophilicity compared with other hydrophobic solvents, and has better compatibility for water phase components and oil phase components, so that the higher yield can be obtained. The control temperature is 20-60 ℃, and the method has good influence on improving the yield and purity.
In example 27, iodine was used as the initiator instead, and the reaction was allowed to take place but in lower yields than dichloroethane. In example 28, however, the solvents of compound I and magnesium were not used in the form of a drop-wise mixture, and therefore, the reaction was vigorous, the temperature was not easily controlled, and the purity and yield were finally lowered.
Further, step S2 is adjusted as shown in the following examples.
Examples 29 to 32
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative is different from example 1 in that in step S2-1, the temperatures are-20℃and 0℃and 10℃and 30℃respectively.
Example 33
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative is different from example 1 in that 100mL of hydrochloric acid with mass fraction of 10% is used as acid I in step S2-2.
Example 34
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative is different from example 1 in that in step S2-2, 100mL of sulfuric acid with mass fraction of 5% is used as acid I.
Example 35
The synthesis method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative is different from example 1 in that in step S2-2, 100mL of phosphoric acid with mass fraction of 10% is used as acid I.
Example 35
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives differs from example 1 in that in step S2-2 it is specifically as follows:
s2-2, adding 100mL of hydrochloric acid (acid I) with mass fraction of 5% into the mixed system IV, preserving heat, standing, separating liquid, preserving an organic phase, evaporating tetrahydrofuran in the organic phase, rectifying the product to obtain clear and transparent liquid, namely 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone.
For examples 29 to 35, the yields and purities of the target products are shown in Table 3.
Table 3: examples 29 to 35 give yields and purities of 3',5' -dichloro-4 ' -amino-2, 2-trifluoroacetophenone
| Example sequence number | Yield rate | Purity of |
| Example 29 | 86.8％ | 99.3％ |
| Examples30 | 87.0％ | 99.2％ |
| Example 31 | 89.4％ | 99.3％ |
| Example 32 | 89.2％ | 99.3％ |
| Example 33 | 89.8％ | 99.1％ |
| Example 34 | 89.1％ | 97.6％ |
| Example 35 | 89.0％ | 98.1％ |
From the above experimental data, in step S2-1, the optimum temperature for the reaction is 10 to 30 ℃, and in step S2, sulfuric acid and phosphoric acid are selected to have poor treatment effect on impurities in the system, resulting in low final purity, and further purification by chromatography or the like is required, compared with 5 to 10% hydrochloric acid.
Further, the following examples were obtained by expanding the applicable range of the reaction based on example 1.
Example 36
Synthetic method of 3',5' -dichloro-2, 2-trifluoroacetophenone derivative for preparing 3',4',5' -trichloro-2, 2-trifluoroacetophenone and implementationExample 1 differs in that in step S1, compound I is 52.1g (0.2 mol) to give 3',4',5' -trichloro-2, 2-trifluoroacetophenone. Specific data of nuclear magnetic resonance hydrogen spectrum: 1H NMR (400 MHz, CDC 1) 3 ):8.05(s,2H)ppm。
Example 37
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives was used to prepare 3',4',5' -trichloro-2, 2-trifluoroacetophenone, which differed from example 1 in that in step S1, compound I was 52.1g (0.2 mol) and compound II was 0.33mol trifluoroacetyl diethylamine (55.8 g).
Example 38
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives for the preparation of 3',5' -dichloro-4 '-fluoro-2, 2-trifluoroacetophenone differs from example 1 in that in step S1 compound I is 48.8g (0.2 mol) 3, 5-dichloro-4-fluorobromobenzene to give 3',4',5' -trichloro-2, 2-trifluoroacetophenone. Specific data of nuclear magnetic resonance hydrogen spectrum: 1H NMR (400 MHz, CDC 1) 3 ):＝8.06(dd,J＝0.8,6.1Hz,2H)。
Example 39
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives for the preparation of 3',5' -dichloro-4 ' -fluoro-2, 2-trifluoroacetophenone differs from example 1 in that in step S1, compound I is 48.8g (0.2 mol) of 3, 5-dichloro-4-fluorobromobenzene and compound II is 0.33mol of trifluoroacetyl diethylamine (55.8 g).
In examples 36 to 39, the yields and purities of the target products are shown in Table 4.
Table 4: examples 36 to 39 yield and purity of the target product
| Example sequence number | Yield rate | Purity of |
| Example 36 | 87.9％ | 99.4％ |
| Example 37 | 84.6％ | 99.1％ |
| Example 38 | 87.2％ | 99.2％ |
| Example 39 | 85.1％ | 99.0％ |
Meanwhile, the following examples were obtained by performing an expansion reaction on example 1, example 36 and example 38.
Example 40
The synthesis method of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative is used for preparing 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone, and the specific preparation process is as follows:
s1, preparing a compound I into a compound II through a Grignard reagent;
s2, reacting the compound II with the compound III, and then carrying out acid treatment to obtain the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative.
Wherein, S1 specifically includes the following steps:
s1-1, weighing 107g of magnesium chips (0.44 mol), adding into a reaction kettle, adding 2.4L of tetrahydrofuran (solvent I), and uniformly stirring at room temperature to obtain a mixed system I;
s1-2, weighing 964g (4 mol) of 3, 5-dichloro-4-aminobromobenzene (compound I), dissolving with 2L of tetrahydrofuran (solvent II) to obtain a mixed system II, and placing the mixed system II in a separating funnel for later use;
s1-3, controlling the temperature of a mixed system I in a reaction bottle to 20 ℃, adding 20ml of 1, 2-dibromoethane as an initiator, uniformly dropwise adding a mixed system II into the mixed system I within 60min, preserving heat at 20 ℃ after dropwise adding, and continuously preserving heat for reaction for 5h to obtain a mixed system III.
The step S2 specifically comprises the following steps:
s2-1, controlling the temperature of the mixed system III obtained in the step S1-3 to 20 ℃, uniformly dropwise adding 932g of trifluoroacetyl dimethylamine (6.6 mol) into the system within 20min, and continuously stirring for 1h after the dropwise adding is finished to obtain a mixed system IV;
s2-2, adding 2L of hydrochloric acid (acid I) with mass fraction of 5% into the mixed system IV, preserving heat, standing, separating liquid, preserving an organic phase, evaporating tetrahydrofuran in the organic phase, rectifying the product to obtain clear and transparent liquid, namely 3',5' -dichloro-4 ' -amino-2, 2-trifluoro acetophenone, wherein the yield is 88.7%, and the purity is 99.6%.
Example 41
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives for the preparation of 3',4',5' -trichloro-2, 2-trifluoroacetophenone was distinguished from example 40 in that compound I was 1040g (4 mol) of 3,4, 5-trichlorobromobenzene; in this example, the yield of 3',4',5' -trichloro-2, 2-trifluoroacetophenone was 87.0% and the purity was 99.2%.
Example 42
The synthesis of 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives was carried out to prepare 3',5' -dichloro-4 '-amino-2, 2-trifluoroacetophenone, which was distinguished from example 40 in that compound I was 976g (4 mol) 3, 5-dichloro-4-fluorobromobenzene, in this example the yield of 3',5 '-dichloro-4' -amino-2, 2-trifluoroacetophenone was 86.1% and the purity was 99.0%.
As is evident from examples 40 to 42, the method of the present application is suitable for mass production, and still has good yield and purity after a large amount of the method is amplified.
For the above examples, reference was made to the preparation methods in the comparative documents, and comparative examples were set as follows:
comparative example 1, a method for synthesizing 3',5' -dichloro-4 ' -amino-2, 2-trifluoroacetophenone, 14.5mL (23.2 mmol) of n-butyllithium was added dropwise to a solution of 5.2g of 3, 5-dichloro-4-aminobromobenzene in tetrahydrofuran (50 mL) at-78℃under nitrogen protection, and the addition was completed in 30 minutes. The reaction was continued with stirring for 1 hour, and then 2.56g of trifluoroacetic anhydride was added dropwise to the above-mentioned mixed system, and the reaction was continued with stirring at-78℃for 2 hours. After subsequent gradual warming to room temperature and further reaction for 2h. After the reaction is completed, 100mL of ammonium chloride is added to terminate the reaction, tetrahydrofuran is removed by separating liquid, diethyl ether is used for extracting water phase, organic phases are combined and washed by saturated saline water, the organic phases are dried by anhydrous magnesium sulfate and filtered, and colorless transparent liquid is obtained by reduced pressure distillation, namely 3',5' -dichloro-2, 2-trifluoro acetophenone. The yield was 40.9% and the purity was 99.1%.
Compared with comparative example 1, the technical scheme adopted in the application has better yield, and the adopted conditions are mild, so that the method has better industrial application prospect.
The present embodiment is only for explanation of the present application and is not to be construed as limiting the present application, and modifications to the present embodiment, which may not creatively contribute to the present application as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present application.
Claims (7)
- The synthesis method of the 3',5' -dichloro-2, 2-trifluoro acetophenone derivative is characterized in that: the method comprises the following steps:s1, preparing a compound I into a compound II through a Grignard reagent;s2, reacting the compound II with the compound III, and then carrying out acid treatment to obtain a 3',5' -dichloro-2, 2-trifluoro acetophenone derivative;compound I is shown below:in the compound I, R1 is NH 2 Either one of F and F;compound II is shown below:compound III is shown below:in the step S1, magnesium metal is selected as the grignard reagent, and the step S1 is specifically as follows:s1-1, dispersing metal magnesium in a solvent I to obtain a mixed system I;s1-2, weighing a compound I, and dissolving the compound I in a solvent II to obtain a mixed system II;s1-3, maintaining the temperature of the mixed system I at 0-100 ℃, adding an initiator into the mixed system, then dropwise adding the mixed system II within 30-60 min after heat preservation, and cooling the reaction system to below 15 ℃ after the dropwise adding is completed and the two are fully reacted to obtain a mixed system III, wherein the mixed system III contains a compound II;wherein R is 2 Is Na (Na) + 、Zn 2+ 、Mg 2+ 、Cu 2+ 、Li + 、K + 、Ca 2+ 、Ni 2+ One of them, and n is R 2 The number of positive charges carried; r is R 3 Is one of Cl, br, F, dimethylamino, diethylamino, piperidinyl, morpholinyl or tetrahydropyrrolyl;the solvent I and the solvent II are tetrahydrofuran, and the total weight of the solvent I and the solvent II is 10 weight percent of the compound IDoubling; the initiator is 1, 2-dibromoethane or iodine.
- 2. The method for synthesizing 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives according to claim 1, wherein the method comprises the following steps: in step S1-3, the reaction temperature is 20-60 ℃.
- 3. The method for synthesizing 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives according to claim 1, wherein the method comprises the following steps: the step S2 is specifically as follows:s2-1, uniformly dropwise adding the compound III into the mixed system III obtained in the step S1-3 within 1-2 h at the temperature of minus 20-30 ℃, and fully reacting after the dropwise adding is finished, so as to obtain a mixed system IV;s2-2, adding acid I into the mixed system IV for acidification, and then further treating to remove a solvent to obtain 3',5' -dichloro-4 ' -R1-2, 2-trifluoro acetophenone;wherein the acid I is any one of sulfuric acid, hydrochloric acid and phosphoric acid.
- 4. A method for synthesizing 3',5' -dichloro-2, 2-trifluoroacetophenone derivatives according to claim 3, wherein: the acid I is hydrochloric acid with the mass fraction of 5-10%.
- 5. The method for synthesizing 3',5' -dichloro-2, 2-trifluoroacetophenone derivative according to claim 3, wherein the temperature is controlled to be 10 to 30℃in step S2-1.
- 6. The method for synthesizing a 3',5' -dichloro-2, 2-trifluoroacetophenone derivative according to any one of claims 1-5, wherein the method comprises the steps of: the compound III is trifluoroacetyl dimethylamine or trifluoroacetyl diethylamine.
- 7. The method for synthesizing a 3',5' -dichloro-2, 2-trifluoroacetophenone derivative according to claim 6, wherein the amount of the trifluoroacetyl group-containing substance in the added compound III is 1.05 to 12.2 times the amount of the compound I.
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