CN117486856A - Synthesis method of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester - Google Patents
Synthesis method of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester Download PDFInfo
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- CN117486856A CN117486856A CN202311445287.4A CN202311445287A CN117486856A CN 117486856 A CN117486856 A CN 117486856A CN 202311445287 A CN202311445287 A CN 202311445287A CN 117486856 A CN117486856 A CN 117486856A
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- trifluoromethyl
- thiophene
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- APRONFJRRDXXRS-UHFFFAOYSA-N methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate Chemical compound COC(=O)C1=CC(Br)=C(C(F)(F)F)S1 APRONFJRRDXXRS-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 150000004820 halides Chemical class 0.000 claims abstract description 12
- YHEBUXDOUNWVNZ-UHFFFAOYSA-M diphenyl(trifluoromethyl)sulfanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[S+](C(F)(F)F)C1=CC=CC=C1 YHEBUXDOUNWVNZ-UHFFFAOYSA-M 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- URPMSPAEAVFKCO-UHFFFAOYSA-N methyl 4,5-dibromothiophene-2-carboxylate Chemical compound COC(=O)C1=CC(Br)=C(Br)S1 URPMSPAEAVFKCO-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- -1 halogenated trifluoromethyl thiophene compound Chemical class 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical class O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 description 1
- VGKLVWTVCUDISO-UHFFFAOYSA-N 3,4-dibromothiophene Chemical compound BrC1=CSC=C1Br VGKLVWTVCUDISO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 101000702559 Homo sapiens Probable global transcription activator SNF2L2 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100031021 Probable global transcription activator SNF2L2 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 1
- 102000003691 T-Type Calcium Channels Human genes 0.000 description 1
- 108090000030 T-Type Calcium Channels Proteins 0.000 description 1
- 102000003610 TRPM8 Human genes 0.000 description 1
- 101150111302 Trpm8 gene Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000012994 photoredox catalyst Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A synthesis method of a compound 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is characterized by comprising the following steps: according to the synthesis method, 4, 5-dibromothiophene-2-methyl formate is used as a raw material, cuprous halide is used as a catalyst, diphenyl (trifluoromethyl) sulfonium triflate is used as a trifluoromethyl reagent, and the reaction is carried out at a selected temperature, so that 4-bromo-5- (trifluoromethyl) thiophene-2-methyl carboxylate is generated with high selectivity. The method has the advantages of high atom economy, simplicity, easiness in operation, high regioselectivity, relatively mild reaction conditions and suitability for industrial scale-up production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester.
Background
As a method for synthesizing the organofluorine compound, there are generally used a method of synthesizing a fluorine compound by addition of an unsaturated C-C bond, a method of synthesizing a fluorine compound by diazonium salt, a method of nucleophilic fluoro, electrophilic fluoro, and a method of introducing trifluoromethyl (trifluoromethylation reaction), and the like. Because of the strong electronegativity, high stability and good fat solubility of trifluoromethyl, the introduction of trifluoromethyl often leads to remarkable changes in the properties of compounds, especially in the physiological activity, and is becoming more and more interesting in the development of new drugs. Therefore, how to introduce trifluoromethyl into a target molecule becomes an important subject in fluorine chemistry. The halogenated trifluoromethyl thiophene compound is an important intermediate and has wide application in the fields of synthesis, medicine and the like. For example, it is used for the synthesis of sulfonamide compounds with TRPM8 antagonistic activity in patent WO 2012/124825; in patent US9403798, it is used for the synthesis of triazinone compounds which have excellent T-type voltage dependent calcium channel inhibiting activity and are particularly useful for the treatment of pain; in patent WO2008/074820A1, it is used for the synthesis of novel oxadiazole derivatives having pharmacological activity, which compounds are useful as S1P1 receptor agonists.
Among such compounds, the compound methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate is used as an important molecular building block in the synthesis of pyridin-2-one compounds, which are useful in the treatment of disorders such as cancer or SMARCA 2-related disorders, as antagonists (e.g. inhibitors) of SMARCA2 in patent WO2020/023657 A1. Therefore, it has a certain meaning to study the synthesis method of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester.
In the prior art, aiming at the synthesis of a similar compound 3, 4-dibromo-2- (trifluoromethyl) thiophene, 3, 4-dibromothiophene is reported as a raw material, mesoporous graphite phase carbon nitride (mpg-CN) is used as a photo-redox catalyst, and a fluoroalkyl reaction is carried out to obtain (Chemistry A European Journal,2015, 21, 526-530). However, the method has complex synthesis operation, can generate sulfur dioxide which is a toxic and harmful gas, and is generally not suitable for process amplification. Therefore, based on the current state of the art, it is necessary to develop a simple and applicable preparation method of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester with relatively mild reaction conditions.
Disclosure of Invention
The invention aims to provide a method for synthesizing 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester, which aims at overcoming the defects of the method for synthesizing 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester, and can generate 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester with high selectivity.
In order to achieve the above object, the present invention provides the following technical solutions:
a method for synthesizing 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is characterized by comprising the following steps: according to the synthesis method, 4, 5-dibromothiophene-2-methyl formate is used as a raw material, cuprous halide is used as a catalyst, diphenyl (trifluoromethyl) sulfonium triflate is used as a trifluoromethyl reagent, and the reaction is carried out at a selected temperature to generate 4-bromo-5- (trifluoromethyl) thiophene-2-methyl carboxylate with high selectivity.
Further, the synthetic route is as follows:
further, it comprises the following steps:
(1) Dissolving a compound 4, 5-dibromothiophene-2-methyl formate in a dry organic solvent I, adding cuprous halide and diphenyl (trifluoromethyl) sulfonium triflate, and reacting at a selected temperature to obtain a reaction solution;
(2) After the raw materials react completely, pouring the reaction solution into water, filtering out solids, collecting liquid, extracting the collected liquid with an organic solvent II, merging organic phases, washing, drying, filtering, and concentrating under reduced pressure to obtain a crude product;
(3) Purifying the crude product to obtain the compound 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester.
Further, in the step (1), the organic solvent I is one or more of N, N-dimethylformamide or N, N-dimethylacetamide or dimethylsulfoxide or toluene or acetone or 1, 3-dimethyl-2-imidazolidinone or hexamethylphosphoric triamide or N-methylpyrrolidone, and still further preferably the organic solvent I is N, N-dimethylformamide.
Further, in the step (1), the cuprous halide CuX is one of cuprous bromide, cuprous iodide and cuprous chloride.
Further, in the step (1), the molar ratio of the methyl 4, 5-dibromothiophene-2-carboxylate, cuprous halide and diphenyl (trifluoromethyl) sulfonium triflate is 1.0: (0.2-1.0): (1.0-3.0); still further preferably the molar ratio of methyl 4, 5-dibromothiophene-2-carboxylate, cuprous halide, diphenyl (trifluoromethyl) sulfonium triflate is 1.0:0.5:1.5.
further, in the step (1), the mass-volume ratio g/mL of the compound methyl 4, 5-dibromothiophene-2-carboxylate to the organic solvent I is 1: (5-40).
Further, in the step (1), the temperature of the reaction is 30-70 ℃; still further preferably the temperature of the reaction is 60 ℃;
further, in the step (1), the reaction time is 2-40h; still further preferred the reaction time is 5-30h, most preferred 12h.
Further, in the step (2), the organic solvent II is selected from one or more of ethyl acetate or butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.
Further, in the step (3), the purification mode comprises one or more of column chromatography, recrystallization and distillation.
The beneficial technical effects of the invention are as follows:
the invention provides a preparation method of 4-bromo-5- (trifluoromethyl) thiophene-2-methyl carboxylate, which takes 4, 5-dibromothiophene-2-methyl carboxylate as a raw material, cuprous halide as a catalyst, diphenyl (trifluoromethyl) sulfonium triflate as a trifluoromethyl reagent, and the reaction is carried out at a selected temperature, so that 4-bromo-5- (trifluoromethyl) thiophene-2-methyl carboxylate is generated with high selectivity. The method has the advantages of high atom economy, simplicity, easiness in operation, high regioselectivity, relatively mild reaction conditions and suitability for industrial scale-up production.
Drawings
FIG. 1 shows the reaction scheme for the synthesis of the target compound methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate in example 1 of the present invention;
FIG. 2 shows nuclear magnetic resonance hydrogen spectra of 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester as a target compound in examples 1 to 10 of the present invention;
Detailed Description
In order to make the technical solution and advantages of the embodiments of the present invention more clear, the technical solution of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
In the following examples, reagents and materials were used as commercially available unless otherwise specified.
The synthesis method of the 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester provided by the embodiment takes 4, 5-dibromothiophene-2-carboxylic acid methyl ester as a raw material, cuprous halide as a catalyst, diphenyl (trifluoromethyl) sulfonium triflate as a trifluoromethyl reagent, and the 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is generated in a high selectivity mode through reaction at a certain temperature.
As shown in the attached figure 1, the synthetic route is as follows:
the invention will be further described by examples and the like.
Example 1
The synthesis of the compound methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate is as follows:
(1) The compound methyl 4, 5-dibromothiophene-2-carboxylate (200.00 g,666.75mmol,1.0 eq) was dissolved in N, N-dimethylformamide (1200 mL) at room temperature, followed by addition of CuBr (47.82 g,133.35mmol,0.5 eq) and diphenyl (trifluoromethyl) sulfonium triflate (404.39 g,1.00mol,1.5 eq). The reaction mixture was stirred at 60℃for 12 hours to give a reaction solution.
(2) After the starting materials were reacted completely, the reaction solution was cooled to room temperature, poured into water (1200 mL), the solid was filtered off with celite and the cake was washed with ethyl acetate (100 ml×2), and the liquid was collected. The collected liquid was extracted three times with ethyl acetate (300 mL x 2), the organic phases were combined, washed 3 times with water (300 mL x 3), once with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product.
(3) The crude product was purified to give 181.00g of methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate as a colorless liquid compound, 97% pure and 91% yield.
The nuclear magnetic resonance hydrogen spectrum of the obtained compound 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is shown in fig. 2, and the obtained characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.44(d,J＝1.1Hz,1H),4.39(q,J＝7.1Hz,2H),1.38(t,J＝7.2Hz,3H).
examples 2 to 10
Examples 2 to 10 are the same as example 1 except that the catalyst, trifluoromethyl reagent, solvent, reaction temperature, solvent and the like used in the reaction are adjusted, and are specifically shown in Table 1.
Comparative example 1
Comparative example 1 was the same as example 1 except that the solvents and the like used in the reaction were adjusted, and specifically, table 1 was presented.
The effect of each reaction condition on the reaction yield in the synthesis of methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate was examined by examples 1 to 10 and comparative example 1, and the reaction results are shown in Table 1.
Table 1 conditions and results for the synthesis of examples and comparative examples
As can be seen in the combination of the above-described graphs,
comparing realityExamples 1, 9, 10 and comparative example 1 in solvent CH 3 The reaction hardly proceeds in CN, and DMF, DMSO and toluene all have promotion effects, wherein DMF is the best solvent.
In comparative examples 1, 4 and 5, the yield of the objective compound was slightly improved when cuprous bromide was used as the catalyst.
Comparative examples 1, 6, 7, 8, reduced the reaction temperature from 60 ℃ to 40 ℃, slowed the reaction rate, and reduced the reaction yield; the reaction temperature is increased from 60 ℃ to 70 ℃, the reaction yield is also reduced, and the reaction at 60 ℃ is more suitable.
In comparative examples 1 to 3, the amount of the catalyst and the trifluoromethyl reagent used was reduced, resulting in deterioration of the conversion rate and a decrease in the reaction yield.
Claims (7)
1. A synthesis method of a compound, namely 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is characterized in that 4, 5-dibromothiophene-2-carboxylic acid methyl ester is used as a raw material, cuprous halide is used as a catalyst, diphenyl (trifluoromethyl) sulfonium triflate is used as a trifluoromethyl reagent, and the reaction is carried out at a selected temperature, so that 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester is generated with high selectivity.
2. The method for synthesizing 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester according to claim 1, wherein the method comprises the following steps:
the synthetic route is as follows:
3. the method for synthesizing 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester according to claim 2, wherein the method comprises the following steps: it comprises the following steps:
(1) Dissolving a compound 4, 5-dibromothiophene-2-methyl formate in a dry organic solvent I, adding cuprous halide and diphenyl (trifluoromethyl) sulfonium triflate, and reacting at a selected temperature to obtain a reaction solution;
(2) After the raw materials react completely, pouring the reaction solution into water, filtering out solids, collecting liquid, extracting the collected liquid with an organic solvent II, merging organic phases, washing, drying, filtering, and concentrating under reduced pressure to obtain a crude product;
(3) Purifying the crude product to obtain the compound 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylic acid methyl ester.
4. A method for synthesizing methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate according to claim 3, wherein: in the step (1), the cuprous halide CuX is one of cuprous bromide, cuprous iodide or cuprous chloride.
5. A method for synthesizing methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate according to claim 3, wherein: in the step (1), the organic solvent I is one or more of N, N-dimethylformamide or N, N-dimethylacetamide or dimethyl sulfoxide or toluene or acetone or 1, 3-dimethyl-2-imidazolidinone or hexamethylphosphoric triamide or N-methylpyrrolidone.
6. A method for synthesizing methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate according to claim 3, wherein: in the step (1), the mole ratio of the methyl 4, 5-dibromothiophene-2-carboxylate, cuprous halide and diphenyl (trifluoromethyl) sulfonium triflate is 1.0: (0.2-1.0): (1.0-3.0);
the mass volume ratio g/mL of the compound 4, 5-dibromothiophene-2-methyl formate to the organic solvent I is 1: (5-40);
the temperature of the reaction is (30-70) DEG C;
the reaction time is (2-40) h.
7. A method for synthesizing methyl 4-bromo-5- (trifluoromethyl) thiophene-2-carboxylate according to claim 3, wherein: in the step (2), the organic solvent II is one or more of ethyl acetate or butyl acetate or chloroform or toluene or methylene dichloride or dichloroethane.
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