CN116693566A - Preparation method of 2-bromo-5-methoxyphenylboronic acid - Google Patents
Preparation method of 2-bromo-5-methoxyphenylboronic acid Download PDFInfo
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- BJQKEDXKQVNQPR-UHFFFAOYSA-N (2-bromo-5-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(Br)C(B(O)O)=C1 BJQKEDXKQVNQPR-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 21
- 238000010791 quenching Methods 0.000 claims abstract description 19
- 230000000171 quenching effect Effects 0.000 claims abstract description 18
- VYNGFCUGSYEOOZ-UHFFFAOYSA-N triphenylphosphine sulfide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=S)C1=CC=CC=C1 VYNGFCUGSYEOOZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 10
- -1 2-bromo-5-methoxyphenylboric acid Chemical compound 0.000 claims abstract description 9
- UEOCICLWNYTZBO-UHFFFAOYSA-N (3-methoxyphenoxy)boronic acid Chemical compound COC1=CC=CC(OB(O)O)=C1 UEOCICLWNYTZBO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 239000012074 organic phase Substances 0.000 claims description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000003208 petroleum Substances 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 235000010265 sodium sulphite Nutrition 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 12
- 238000004440 column chromatography Methods 0.000 abstract description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 5
- 229960002317 succinimide Drugs 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012047 saturated solution Substances 0.000 description 7
- 229940001482 sodium sulfite Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- LPEHQJGMIUSOGA-UHFFFAOYSA-N butane-1,2-diimine Chemical compound CCC(=N)C=N LPEHQJGMIUSOGA-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps: 3-methoxyphenylboric acid, triphenylphosphine sulfide and N-bromosuccinimide are mixed for reaction, and after the reaction, the 2-bromo-5-methoxyphenylboric acid is obtained through quenching, washing, drying and crystallization. In the post-treatment, column chromatography is not needed for separation, redundant N-bromosuccinimide is consumed through quenching, washing is carried out to remove the by-product succinimide generated by the reaction, an organic solvent is added for crystallization, and the 2-bromo-5-methoxyphenylboric acid obtained by filtration is prepared, so that the purification process is simple and is suitable for the preparation of a large amount of 2-bromo-5-methoxyphenylboric acid.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of 2-bromo-5-methoxyphenylboronic acid.
Background
The 2-bromo-5-methoxyphenylboronic acid can be used as an intermediate for pharmaceutical synthesis and can be prepared from 3-methoxyphenylboronic acid, triphenylphosphine sulfide and N-bromosuccinimide.
The conventional method for preparing 2-bromo-5-methoxyphenylboronic acid is worked up by adding a saturated aqueous solution of sodium thiosulfate to the reaction mixture to terminate the reaction, extracting with methylene chloride, washing the combined organic layers with saturated brine, then drying over sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (n-hexane/acetone=1/1) to give 2-bromo-5-methoxyphenylboronic acid. The post-treatment for preparing the 2-bromo-5-methoxyphenylboronic acid conventionally requires a column, is relatively complicated to process, is not suitable for mass production, requires a large amount of organic solvents for column chromatography separation when processing a large amount of samples, generates more wastes, is relatively expensive, consumes relatively long time, and is not suitable for industrial production.
The method for preparing the 2-bromo-5-methoxyphenylboronic acid has the problems that the separation step by column chromatography is needed, the purification method is complex, and the mass purification is difficult. Therefore, developing a preparation method which does not require column chromatography separation, is simple in purification method and can be purified in a large amount is a problem to be solved in the art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 2-bromo-5-methoxyphenylboronic acid, wherein the 2-bromo-5-methoxyphenylboronic acid with higher purity can be obtained by post-treatment in the preparation method without column chromatography separation, and the purification process is simple and is suitable for mass production.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
the invention provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps:
3-methoxyphenylboric acid, triphenylphosphine sulfide and N-bromosuccinimide are mixed for reaction, and after the reaction, the 2-bromo-5-methoxyphenylboric acid is obtained through quenching, washing, drying and crystallization.
The preparation method of the 2-bromo-5-methoxyphenylboronic acid provided by the invention comprises the following steps:
preferably, the reaction is carried out in the presence of a solvent.
Preferably, the solvent comprises dichloromethane.
Preferably, the molar ratio of 3-methoxyphenylboronic acid to triphenylphosphine is 1 (0.05-0.15), and may be, for example, 1:0.05, 1:0.08, 1:0.1, 1:0.12, 1:0.15, and specific point values between the above point values, although the invention is limited in scope and for brevity, the invention is not intended to be exhaustive of the specific point values included in the ranges.
Preferably, the molar ratio of 3-methoxyphenylboronic acid to N-bromosuccinimide (NBS) is 1 (1.1-1.3), and may be, for example, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, and specific point values between the above point values, which are not exhaustive for the sake of brevity and conciseness.
Preferably, the temperature of the reaction is 20-30 ℃, for example, 20 ℃, 22 ℃, 25 ℃, 28 ℃, 30 ℃, and specific values between the above values, are not exhaustive of the specific values included in the range for reasons of space and for reasons of simplicity.
Preferably, the reaction time is 40-50h, for example 40h, 42h, 45h, 48h, 50h, and specific point values between the above point values, although for reasons of length and brevity, the invention is not intended to be exhaustive of the specific point values included in the range.
Preferably, the N-bromosuccinimide is added at a temperature of-5 to 5 ℃, for example, -5 ℃, -3 ℃, 0 ℃,3 ℃,5 ℃, and specific values between the above, and the present invention is not exhaustive of the specific values included in the range for reasons of space and for reasons of simplicity.
Preferably, the quenching comprises quenching with the addition of sodium sulfite.
Preferably, the sodium sulfite is an aqueous solution of sodium sulfite.
The aqueous solution of sodium sulfite is a saturated aqueous solution of sodium sulfite.
N-bromosuccinimide is oxidative, and can be quenched with an aqueous solution of sodium sulfite to consume excess N-bromosuccinimide.
Preferably, the washing includes solvent washing and water washing.
Preferably, the solvent washing comprises washing with an aqueous solution of sodium bicarbonate.
The aqueous solution of sodium bicarbonate is saturated aqueous solution of sodium bicarbonate.
Bromine on N-bromosuccinimide can generate butanediimine, the butanediimine is an acidic substance, and sodium bicarbonate can be dissolved in an aqueous phase after neutralization to form salt so as to remove the butanediimine.
Preferably, the drying comprises drying using anhydrous sodium sulfate.
Preferably, the crystallization comprises adding an organic solvent for crystallization and filtering.
Preferably, the organic solvent comprises any one or a combination of at least two of petroleum ether, n-hexane or dichloromethane.
Preferably, the volume ratio of the organic solvent to the dried organic phase is (1.3-1.7): 1, which may be, for example, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, and specific point values between the above point values, are for brevity and for simplicity, the present invention is not intended to be exhaustive of the specific point values encompassed by the described ranges.
The volume ratio of the organic solvent to the dried organic phase is (1.3-1.7): 1 is more suitable, and too much can precipitate triphenylphosphine together, and too little product will not precipitate.
Preferably, the preparation method specifically comprises the following steps:
mixing 3-methoxyphenylboric acid, triphenylphosphine and N-bromosuccinimide, reacting for 40-50 hours at 20-30 ℃, then quenching sodium sulfite, washing with any one or a combination of at least two of petroleum ether, normal hexane and methylene dichloride, washing with water, drying with anhydrous sodium sulfate, adding an organic solvent for crystallization, and filtering to obtain the 2-bromo-5-methoxyphenylboric acid.
Compared with the prior art, the invention has the following beneficial effects:
according to the preparation method of the 2-bromo-5-methoxyphenylboronic acid, column chromatography is not needed for separation in post-treatment, redundant NBS is consumed through quenching, washing is carried out to remove the byproduct succinimide generated by the reaction, and the 2-bromo-5-methoxyphenylboronic acid with higher purity is obtained through adding an organic solvent for crystallization and filtering.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 2-bromo-5-methoxyphenylboronic acid obtained in example 1;
FIG. 2 is a LCMS diagram of 2-bromo-5-methoxyphenylboronic acid obtained in example 1;
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The embodiment provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps:
3-methoxyphenylboric acid (470 g), triphenylphosphine sulfide (91 g) and methylene chloride are added into a reaction kettle and cooled to zero, NBS (660 g) is added in batches, the mixture is reacted at 25 ℃ for 48 hours, samples are taken, after saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, an organic phase is washed once by saturated sodium bicarbonate solution and then once by water, the organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.5V of petroleum ether is added into the organic phase in batches according to 1V of the volume of the organic phase, a large amount of white solid is separated out, and a filter cake is the 2-bromo-5-methoxyphenylboric acid, 475g of white solid, and the yield is 66.5%.
The 2-bromo-5-methoxyphenylboronic acid provided by this example was subjected to structural characterization, nuclear magnetic resonance spectroscopy was performed using a Bruce Bruker Ultrashield 400plus 400MHz nuclear magnetic resonance spectrometer, the nuclear magnetic hydrogen spectrum obtained was as shown in FIG. 1, 1 H NMR(400MHz,CDCl 3 ) Delta 7.47 (dd, j=17.6, 6.0hz, 2H), 6.89 (dd, j=8.8, 3.3hz, 1H), 5.43 (s, 2H), 3.84 (s, 3H), indicating the product obtained as 2-bromo-5-methoxyphenylboronic acid.
The 2-bromo-5-methoxyphenylboronic acid provided in this example was subjected to structural characterization, and was tested using an Agilent liquid chromatography-Mass Spectrometry (MS) with a purity of 97% as shown in FIG. 2.
Example 2
The embodiment provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps:
3-methoxyphenylboronic acid (470 g), triphenylphosphine sulfide (100 g) and methylene chloride are added into a reaction kettle and cooled to zero, NBS (600 g) is added in batches, the mixture is reacted at 25 ℃ for 48 hours, samples are taken, after saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, an organic phase is washed once by saturated sodium bicarbonate solution and then once by water, the organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.5V of petroleum ether is added into the organic phase in batches according to 1V of the volume of the organic phase, a large amount of white solid is separated out, and a filter cake is the 2-bromo-5-methoxyphenylboronic acid with 460g of white solid, and the yield is 64.4%.
Example 3
The embodiment provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps:
3-methoxyphenylboric acid (470 g), triphenylphosphine sulfide (91 g) and methylene chloride are added into a reaction kettle and cooled to zero, NBS (660 g) is added in batches, the mixture is reacted at 30 ℃ for 40 hours, samples are taken, saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, an organic phase is washed once by saturated sodium bicarbonate solution and then once by water, the organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.5V of petroleum ether is added into the organic phase in batches according to 1V of the volume of the organic phase, a large amount of white solid is separated out, and a filter cake is the 2-bromo-5-methoxyphenylboric acid, 447.9g of white solid, and the yield is 62.7%.
Example 4
The embodiment provides a preparation method of 2-bromo-5-methoxyphenylboronic acid, which comprises the following steps:
3-methoxyphenylboronic acid (470 g), triphenylphosphine sulfide (100 g) and methylene chloride are added into a reaction kettle and cooled to zero, NBS (660 g) is added in batches, the mixture is reacted at 25 ℃ for 40 hours, samples are taken, saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, an organic phase is washed once by saturated sodium bicarbonate solution and then once by water, the organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.5V of methylene chloride is added into the organic phase in batches according to 1V of the volume of the organic phase, a large amount of white solid is separated out, and a filter cake is 2-bromo-5-methoxyphenylboronic acid, 453.6g of white solid is obtained, and the yield is 63.5%.
Comparative example 1
This comparative example provides a process for the preparation of 2-bromo-5-methoxyphenylboronic acid, comprising:
3-Methoxyphenylboronic acid (470 g), triphenylphosphine sulfide (91 g) and methylene dichloride are added into a reaction kettle to be cooled to zero, NBS (660 g) is added in batches, the mixture is reacted at 25 ℃ for 48 hours, sampling is carried out, a saturated sodium sulfite quenching point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted completely, an anhydrous sodium sulfite saturated solution is added into the reaction kettle to quench, and then the mixture is separated and passes through a column (petroleum ether PE: ethyl acetate EA=3:1), 435.7g of white solid is obtained, and the yield is 61%.
Comparative example 2
This comparative example provides a process for the preparation of 2-bromo-5-methoxyphenylboronic acid, comprising:
3-methoxyphenylboronic acid (470 g), triphenylphosphine sulfide (180 g) and methylene chloride are added into a reaction kettle and cooled to zero, NBS (660 g) is added in batches, the mixture is reacted at 25 ℃ for 40 hours, samples are taken, after saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, an organic phase is washed once by saturated sodium bicarbonate solution and then once by water, the organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.2V of petroleum ether is added into the organic phase in batches according to 1V of the volume of the organic phase, a large amount of white solid is separated out, and a filter cake is the 2-bromo-5-methoxyphenylboronic acid with 400g of white solid, and the yield is 56%.
Comparative example 3
This comparative example provides a process for the preparation of 2-bromo-5-methoxyphenylboronic acid, comprising:
3-methoxyphenylboric acid (470 g), triphenylphosphine sulfide (91 g) and methylene dichloride are added into a reaction kettle, the temperature is reduced to zero, NBS (660 g) is added in batches, the mixture is reacted at 25 ℃ for 48 hours, samples are taken, saturated sodium sulfite is quenched, a point plate (petroleum ether PE: ethyl acetate EA=3:1) raw material is reacted, anhydrous sodium sulfite saturated solution is added into the reaction kettle for quenching, liquid separation is carried out, water is used for washing once, an organic phase is dried by anhydrous sodium sulfate, anhydrous sodium sulfate is removed, 1.5V of petroleum ether is added in batches in terms of the volume of the organic phase, a large amount of white solid is precipitated, and filtration is carried out, so that impurity succinimide is precipitated together.
According to examples 1-4, comparative examples 1-3 showed that the NBS use amount of 1.1-1.3 equivalent had no effect on the yield, and that an increase in the amount of triphenylphosphine sulfide used reduced the reaction time by a small amount, and that the reduction step resulted in a partial impurity which could not be removed, and that the column passing yield and crystallization yield were low; meanwhile, the examples 1-4 are more suitable for preparing a large amount of 2-bromo-5-methoxyphenylboronic acid, meet the green chemical requirements, save funds and reduce the use and production of dangerous substances.
The applicant states that the process of the invention is illustrated by the above examples, but the invention is not limited to, i.e. does not mean that the invention must be carried out in dependence on the above process steps. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of selected raw materials, addition of auxiliary components, selection of specific modes, etc. fall within the scope of the present invention and the scope of disclosure.
Claims (10)
1. A method for preparing 2-bromo-5-methoxyphenylboronic acid, comprising the steps of:
3-methoxyphenylboric acid, triphenylphosphine sulfide and N-bromosuccinimide are mixed for reaction, and after the reaction, the 2-bromo-5-methoxyphenylboric acid is obtained through quenching, washing, drying and crystallization.
2. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent;
preferably, the solvent comprises dichloromethane;
preferably, the molar ratio of the 3-methoxyphenylboronic acid to the triphenylphosphine sulfide is 1 (0.05-0.15);
preferably, the molar ratio of the 3-methoxyphenylboronic acid to the N-bromosuccinimide is 1 (1.1-1.3).
3. The preparation method according to claim 1 or 2, wherein the temperature of the reaction is 20-30 ℃;
preferably, the reaction time is 40-50 hours.
4. A process according to any one of claims 1 to 3, wherein the N-bromosuccinimide is added at a temperature of-5 to 5 ℃.
5. The method of any one of claims 1-4, wherein the quenching comprises quenching with the addition of sodium sulfite;
preferably, the sodium sulfite is an aqueous solution of sodium sulfite.
6. The method according to any one of claims 1 to 5, wherein the washing comprises solvent washing and water washing;
preferably, the solvent washing comprises washing with an aqueous solution of sodium bicarbonate.
7. The method of any one of claims 1-6, wherein the drying comprises drying with anhydrous sodium sulfate.
8. The method according to any one of claims 1 to 7, wherein the crystallization comprises crystallization by adding an organic solvent and filtration.
9. The method according to claim 8, wherein the organic solvent comprises any one or a combination of at least two of petroleum ether, n-hexane, or dichloromethane;
preferably, the volume ratio of the organic solvent to the dried organic phase is (1.3-1.7): 1.
10. the preparation method according to any one of claims 1 to 9, characterized in that it comprises in particular the following steps:
mixing 3-methoxyphenylboric acid, triphenylphosphine sulfide and N-bromosuccinimide, reacting for 40-50 hours at 20-30 ℃, then quenching sodium sulfite, washing with sodium bicarbonate aqueous solution, washing with water, drying with anhydrous sodium sulfate, adding an organic solvent for crystallization, and filtering to obtain the 2-bromo-5-methoxyphenylboric acid.
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