CN112321621A - Preparation method of 3-chlorobenzene boric acid - Google Patents
Preparation method of 3-chlorobenzene boric acid Download PDFInfo
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- CN112321621A CN112321621A CN202011333674.5A CN202011333674A CN112321621A CN 112321621 A CN112321621 A CN 112321621A CN 202011333674 A CN202011333674 A CN 202011333674A CN 112321621 A CN112321621 A CN 112321621A
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- boric acid
- grignard reagent
- chlorobenzene
- chlorobenzene boric
- ether
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- XLGLMVCAOMQNJT-UHFFFAOYSA-N boric acid;chlorobenzene Chemical compound OB(O)O.ClC1=CC=CC=C1 XLGLMVCAOMQNJT-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 36
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000001816 cooling Methods 0.000 claims abstract description 24
- -1 boric acid ester Chemical class 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- JRGGUPZKKTVKOV-UHFFFAOYSA-N 1-bromo-3-chlorobenzene Chemical compound ClC1=CC=CC(Br)=C1 JRGGUPZKKTVKOV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 238000004537 pulping Methods 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- 239000012065 filter cake Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000004327 boric acid Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- 239000012043 crude product Substances 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 238000010438 heat treatment Methods 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- SDEAGACSNFSZCU-UHFFFAOYSA-N (3-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1 SDEAGACSNFSZCU-UHFFFAOYSA-N 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- MLSKXPOBNQFGHW-UHFFFAOYSA-N methoxy(dioxido)borane Chemical group COB([O-])[O-] MLSKXPOBNQFGHW-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- RWNUSVWFHDHRCJ-UHFFFAOYSA-N 1-butoxypropan-2-ol Chemical compound CCCCOCC(C)O RWNUSVWFHDHRCJ-UHFFFAOYSA-N 0.000 claims description 2
- JOLQKTGDSGKSKJ-UHFFFAOYSA-N 1-ethoxypropan-2-ol Chemical compound CCOCC(C)O JOLQKTGDSGKSKJ-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- SURBAJYBTYLRMQ-UHFFFAOYSA-N dioxido(propan-2-yloxy)borane Chemical compound CC(C)OB([O-])[O-] SURBAJYBTYLRMQ-UHFFFAOYSA-N 0.000 claims description 2
- KUGSJJNCCNSRMM-UHFFFAOYSA-N ethoxyboronic acid Chemical compound CCOB(O)O KUGSJJNCCNSRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 15
- 238000003747 Grignard reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract description 2
- 239000010865 sewage Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- JGRXMPYUTJLTKT-UHFFFAOYSA-N 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid Chemical compound C1=C(O)C(C(=O)NCC(=O)O)=NC=C1C1=CC=CC(Cl)=C1 JGRXMPYUTJLTKT-UHFFFAOYSA-N 0.000 description 1
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical group [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 description 1
- CZTRCGMJNUHYEL-UHFFFAOYSA-M [Cl-].[Mg+]C1=CC=CC(Cl)=C1 Chemical compound [Cl-].[Mg+]C1=CC=CC(Cl)=C1 CZTRCGMJNUHYEL-UHFFFAOYSA-M 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ALINVVBOLJMYOC-UHFFFAOYSA-N bromobenzene;hydrochloride Chemical compound Cl.BrC1=CC=CC=C1 ALINVVBOLJMYOC-UHFFFAOYSA-N 0.000 description 1
- 150000004768 bromobenzenes Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000017168 chlorine Nutrition 0.000 description 1
- 125000001309 chloro group Chemical class Cl* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 229950004420 vadadustat Drugs 0.000 description 1
- 239000003643 water by type Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis, and particularly discloses a preparation method of 3-chlorobenzene boric acid, which comprises the steps of preparing 3-chlorobenzene boric acid by taking m-bromochlorobenzene as a raw material, preparing a Grignard reaction reagent, reacting with boric acid ester to generate the 3-chlorobenzene boric acid ester, hydrolyzing the 3-chlorobenzene boric acid ester by acid to obtain a crude product, and performing gradient cooling crystallization, filtration, ether solvent pulping and filter cake washing on the crude product to obtain a product with the purity of more than 99.5 percent and less than 0.1 percent of single impurity, so that the purity requirement of a pharmaceutical intermediate in the production process of raw medicines is met. In addition, the 3-chlorobenzene boric acid synthesized by the method has the total yield of more than 70 percent, which is obviously superior to the yield of the existing Grignard reagent method; the intermediate product Grignard reagent can be directly used for the next reaction without separation, thereby effectively simplifying the process, reducing the sewage discharge and lowering the cost.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 3-chlorobenzene boric acid.
Background
3-chlorobenzeneboronic acid of formula C6H6BClO2The structural formula is as follows:
3-Chlorobenzeneboronic acid is an important pharmaceutical intermediate, and can be used for synthesizing a novel drug for treating anemia, Vadadustat (Vatustat).
The traditional preparation method of 3-chlorobenzene boric acid mainly comprises an organolithium method and a Grignard reagent method, wherein the organolithium method is generally that substituted bromobenzene firstly carries out lithium-bromine exchange reaction with alkyl lithium to obtain substituted lithiumbenzene, then the substituted lithiumbenzene is reacted with trialkyl borate, and the corresponding substituted phenylboronic acid is obtained by hydrolysis, wherein the reaction formula is as follows:
the organic lithium method has high yield and few byproducts, but the method has high operation safety and danger and high price of alkyl lithium, and is not suitable for industrial production.
Compared with an organic lithium method, the Grignard reagent method has good safety and low cost, is a commonly used method for synthesizing 3-chlorobenzene boric acid in industry, and mainly takes m-dichlorobenzene as a raw material to perform Grignard reaction with metal magnesium to generate 3-chlorphenyl magnesium chloride, and the product of the Grignard reaction is hydrolyzed with trialkyl borate to obtain the 3-chlorobenzene boric acid, wherein the reaction formula is as follows:
the method has the advantages that two chlorines are arranged on the m-dichloro benzene ring of the raw material, the Grignard reagent can be formed, disubstituted impurities are easy to generate, the separation and purification are difficult, and the purity of the product 3-chlorobenzene boric acid is directly influenced. In addition, the yield of the conventional Grignard reagent method is not high, and the product yield is only about 55% when the Grignard reagent method is adopted to synthesize the 3-chlorobenzeneboronic acid in patent application CN 109232620A.
In all the synthesis methods, although refined for 2-3 times, the purity of the 3-chlorobenzene boric acid is still lower than 99%, and the single impurity exceeds 0.2%, so that the purity of the 3-chlorobenzene boric acid cannot meet the requirement of being used as a medical intermediate (the purity is not lower than 99.0%, and the single impurity is not higher than 0.20%). Therefore, a method capable of producing high-purity 3-chlorobenzeneboronic acid with high yield is urgently needed.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of 3-chlorobenzene boric acid, which can obtain high-purity 3-chlorobenzene boric acid (the purity is more than 99.5 percent, and the single impurity is less than 0.10 percent), and the total yield is more than 70 percent.
In order to achieve the purpose, the invention adopts the following specific technical scheme:
a preparation method of 3-chlorobenzene boric acid adopts the following synthetic route: 3-chloro-1-bromobenzene is used as a raw material and reacts with magnesium to prepare Grignard reagent 3-chlorphenyl magnesium bromide; then reacting the Grignard reagent with boric acid ester to generate 3-chlorobenzene boric acid ester; 3-chlorobenzene boric acid ester is hydrolyzed by acid to generate 3-chlorobenzene boric acid. The reaction formula is as follows (taking boric acid ester as methyl borate for example):
the invention improves the existing Grignard reagent method, takes 3-chloro-1-bromobenzene (hereinafter abbreviated as m-bromochlorobenzene) as a raw material, and the bromobenzene can more easily form the Grignard reagent, thereby avoiding the generation of disubstituted impurities and effectively improving the product purity.
Preferably, the borate ester is methyl borate, ethyl borate or isopropyl borate.
Preferably, the crude product obtained by acid hydrolysis of the 3-chlorobenzene boric acid ester is separated and purified by adopting a gradient cooling crystallization and ether solvent pulping mode, and then the high-purity 3-chlorobenzene boric acid product is obtained.
Preferably, the temperature reduction speed of the gradient temperature reduction crystallization is controlled to be 0.5-20 ℃/hour.
Preferably, the ether solvent is petroleum ether, methyl tert-butyl ether, isopropyl ether, propylene glycol methyl ether, propylene glycol ethyl ether or propylene glycol butyl ether.
Preferably, the preparation method of the 3-chlorobenzene boric acid specifically comprises the following steps:
preparation of a Grignard reagent
Under the protection of nitrogen, adding magnesium strips, anhydrous tetrahydrofuran and iodine into a reaction container, heating until the tetrahydrofuran boils, starting to reflux, stopping heating, dropwise adding a mixed solution of m-chlorobromobenzene and tetrahydrofuran, and carrying out reflux reaction for 4-6 h to obtain a Grignard reagent solution;
synthesis of di, 3-chlorobenzene boric acid
Under the protection of nitrogen, dropwise adding the prepared Grignard reagent solution into a mixed solution of tetrahydrofuran and boric acid ester, keeping the reaction temperature at-35 to-45 ℃, continuously stirring and reacting after the Grignard reagent solution is completely added until all precipitates are dissolved, and then heating the reaction mixture to 0-4 ℃ in a cold water bath;
adding 10% sulfuric acid into the reaction mixture under stirring, standing for layering, separating organic layer, extracting water layer with ether solvent, mixing organic layers, drying with anhydrous sodium sulfate, and filtering;
and distilling the filtrate under reduced pressure, recovering the solvent, adding water, heating to 96-99 ℃, cooling to 55-65 ℃ at the speed of 0.5-20 ℃/h, preserving heat for 0.5-1.5 hours, cooling to 15-25 ℃ at the speed of 0.5-20 ℃/h, preserving heat for 0.5-1.5 hours, pulping and washing a filter cake with petroleum ether, filtering, and drying to obtain a finished product.
Preferably, in the second step, the gradient temperature-reduction crystallization process is as follows: adding water into the filtrate, heating to 98 ℃, cooling to 60 ℃ at a speed of 0.5-20 ℃/h, preserving heat for 1 hour, cooling to 20 ℃ at a speed of 0.5-20 ℃/h, and preserving heat for 1 hour.
Preferably, in step two, the filter cake is washed at least twice by beating with petroleum ether.
The invention also provides application of the 3-chlorobenzene boric acid prepared by the preparation method of the 3-chlorobenzene boric acid, which is used as a medical intermediate for synthesizing the valdoxetamol.
The invention has the following beneficial effects:
1. the invention provides a new synthesis path of 3-chlorobenzene boric acid, and the preparation of the Grignard reagent by using m-bromochlorobenzene as a raw material can avoid the generation of disubstituted impurities and effectively improve the product purity.
2. The invention adopts a new synthesis path, and carries out gradient cooling crystallization and ether solvent pulping post-treatment on the crude product, so that the purity of the product reaches more than 99.5 percent, and the single impurity is less than 0.10 percent, thereby meeting the requirement of the production process of the raw material medicine on the high purity of the pharmaceutical intermediate.
3. The 3-chlorobenzene boric acid synthesized by the method has the total yield of over 70 percent, and compared with the existing Grignard reagent method, the yield is obviously improved.
4. The intermediate product Grignard reagent can be directly used for the next reaction without separation, thereby effectively simplifying the process, reducing the sewage discharge and lowering the cost.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
A preparation method of 3-chlorobenzene boric acid specifically comprises the following steps:
preparation of a Grignard reagent
Under the protection of nitrogen, adding magnesium strips (3.361 g, 0.14 mol), 50mL of anhydrous tetrahydrofuran and a small amount of iodine (0.020 g, 0.158 mmol) into a 250 mL four-neck round-bottom flask, slowly heating until the tetrahydrofuran boils, starting refluxing, stopping heating, slowly dropwise adding a mixed solution of m-chlorobromobenzene (23.875 g, 0.125 mol) and 85 mL of tetrahydrofuran, and carrying out reflux reaction for 5 hours to obtain a Grignard reagent solution; the yield (calculated by m-chlorobromobenzene) measured by an acid titration method is 96.3 percent;
synthesis of di, 3-chlorobenzene boric acid
Under the protection of nitrogen, slowly and dropwise adding the prepared Grignard reagent solution into a mixed solution of 100mL tetrahydrofuran and 22.2 g trimethyl borate, keeping the reaction temperature at-40 ℃, continuously stirring and reacting until all precipitates are dissolved after the Grignard reagent solution is added, and then slowly heating the reaction mixture to 0 ℃ in a cold water bath;
adding 100mL of cold 10% sulfuric acid into the reaction mixture in a cooling trap under vigorous stirring, standing for layering, separating organic layers, extracting the aqueous layer with methyl tert-butyl ether (20 mL × 3), combining the organic layers, drying with anhydrous sodium sulfate, and filtering;
distilling the filtrate under reduced pressure to recover the solvent, distilling out methanol, adding 300ml of water, heating to 98 ℃, cooling to 60 ℃ at a speed of 3-5 ℃/h, preserving heat for 1 hour, cooling to 20 ℃ at a speed of 3-5 ℃/h, preserving heat for 1 hour, pulping and washing a filter cake twice by using 50ml of petroleum ether, filtering, and drying to obtain 14.37 g of a finished product (the yield is 72.8 percent in terms of m-chlorobromobenzene); the purity of the 3-chlorobenzene boric acid finished product is 99.88 percent, the maximum single impurity is 0.06 percent, and the total impurity is 0.12 percent by HPLC method.
Example 2
A preparation method of 3-chlorobenzene boric acid specifically comprises the following steps:
preparation of a Grignard reagent
Under the protection of nitrogen, adding magnesium strips (3.361 g, 0.14 mol), 50mL of anhydrous tetrahydrofuran and a small amount of iodine (0.020 g, 0.158 mmol) into a 250 mL four-neck round-bottom flask, slowly heating until the tetrahydrofuran boils, starting refluxing, stopping heating, slowly dropwise adding a mixed solution of m-chlorobromobenzene (23.875 g, 0.125 mol) and 85 mL of tetrahydrofuran, and carrying out reflux reaction for 5 hours to obtain a Grignard reagent solution; the yield (calculated by m-chlorobromobenzene) measured by an acid titration method is 97.8 percent;
synthesis of di, 3-chlorobenzene boric acid
Under the protection of nitrogen, slowly and dropwise adding the prepared Grignard reagent solution into a mixed solution of 100mL tetrahydrofuran and 34.2 g triisopropyl borate, keeping the reaction temperature at-40 ℃, continuously stirring and reacting until all precipitates are dissolved after the Grignard reagent solution is added, and then slowly heating the reaction mixture to 0 ℃ in a cold water bath;
adding 100mL of cold 10% sulfuric acid into the reaction mixture in a cooling trap under vigorous stirring, standing for layering, separating organic layers, extracting the aqueous layer with methyl tert-butyl ether (20 mL × 3), combining the organic layers, drying with anhydrous sodium sulfate, and filtering;
distilling the filtrate under reduced pressure to recover the solvent, adding 300ml of water, heating to 98 ℃, cooling to 60 ℃ at a speed of 8-10 ℃/h, preserving heat for 1 h, cooling to 20 ℃ at a speed of 8-10 ℃/h, preserving heat for 1 h, pulping and washing a filter cake twice by using 50ml of methyl tert-butyl ether, filtering, and drying to obtain 15.10 g of a finished product (the yield is 76.5 percent in terms of m-chlorobromobenzene); the purity of the 3-chlorobenzene boric acid finished product is 99.81 percent, the maximum single impurity is 0.07 percent, and the total impurity is 0.19 percent by HPLC method.
Example 3
A preparation method of 3-chlorobenzene boric acid specifically comprises the following steps:
preparation of a Grignard reagent
Under the protection of nitrogen, adding magnesium strips (3.361 g, 0.14 mol), 50mL of anhydrous tetrahydrofuran and a small amount of iodine (0.020 g, 0.158 mmol) into a 250 mL four-neck round-bottom flask, slowly heating until the tetrahydrofuran boils, starting refluxing, stopping heating, slowly dropwise adding a mixed solution of m-chlorobromobenzene (23.875 g, 0.125 mol) and 85 mL of tetrahydrofuran, and carrying out reflux reaction for 5 hours to obtain a Grignard reagent solution; the yield (calculated by m-chlorobromobenzene) measured by an acid titration method is 97.3 percent;
synthesis of di, 3-chlorobenzene boric acid
Under the protection of nitrogen, slowly and dropwise adding the prepared Grignard reagent solution into a mixed solution of 100mL tetrahydrofuran and 43.2 g tributyl borate, keeping the reaction temperature at-40 ℃, continuously stirring and reacting until all precipitates are dissolved after the Grignard reagent solution is added, and then slowly heating the reaction mixture to 0 ℃ in a cold water bath;
adding 100mL of cold 10% sulfuric acid into the reaction mixture in a cooling trap under vigorous stirring, standing for layering, separating organic layers, extracting the aqueous layer with methyl tert-butyl ether (20 mL × 3), combining the organic layers, drying with anhydrous sodium sulfate, and filtering;
distilling the filtrate under reduced pressure to recover the solvent, adding 300ml of water, heating to 98 ℃, cooling to 60 ℃ at a speed of 10-15 ℃/h, preserving heat for 1 h, cooling to 20 ℃ at a speed of 10-15 ℃/h, preserving heat for 1 h, pulping and washing a filter cake twice by using 50ml of isopropyl ether, filtering, and drying to obtain a finished product of 14.86 g (the yield is 75.3 percent in terms of bromobenzene chloride); the purity of the 3-chlorobenzene boric acid finished product is 99.89 percent, the maximum single impurity is 0.05 percent, and the total impurity is 0.11 percent by HPLC method.
Note: the chromatographic conditions for determining purity and impurity content by HPLC method in examples 1-3 are:
chromatographic column Waters Cortecs C18(150mm 4.6mm 2.7 um)
Wavelength UV 220 nm
Column temperature 35 deg.C
The temperature of the sample injection disc is 20 DEG C
Flow rate 1.0 mL/min
Sample introduction volume of 5 mu L
Mobile phase: a, measuring 1mL of TEA into 900L of water, adjusting the pH value to 7.5 by phosphoric acid, metering the volume to 1L by water, uniformly mixing, and filtering twice
B: MeOH
A:B=20:80(V/V)
Area normalization method.
This detailed description is to be construed as illustrative only and is not to be taken as limiting the invention, as any changes that may be made by a person skilled in the art after reading the present specification will be protected by the patent laws within the scope of the appended claims.
Claims (9)
1. A preparation method of 3-chlorobenzene boric acid is characterized by comprising the following steps: the following synthetic route was used: 3-chloro-1-bromobenzene is used as a raw material and reacts with magnesium to prepare Grignard reagent 3-chlorphenyl magnesium bromide; then reacting the Grignard reagent with boric acid ester to generate 3-chlorobenzene boric acid ester; 3-chlorobenzene boric acid ester is hydrolyzed by acid to generate 3-chlorobenzene boric acid.
2. The method for producing 3-chlorobenzeneboronic acid according to claim 1, wherein: the boric acid ester is methyl borate, ethyl borate or isopropyl borate.
3. The method for producing 3-chlorobenzeneboronic acid according to claim 1, wherein: the crude product obtained by acid hydrolysis of the 3-chlorobenzene boric acid ester is separated and purified by adopting a gradient cooling crystallization and ether solvent pulping mode.
4. The method for producing 3-chlorobenzeneboronic acid according to claim 3, characterized in that: the cooling speed of the gradient cooling crystallization is controlled to be 0.5-20 ℃/hour.
5. The method for producing 3-chlorobenzeneboronic acid according to claim 3, characterized in that: the ether solvent is petroleum ether, methyl tert-butyl ether, isopropyl ether, propylene glycol methyl ether, propylene glycol ethyl ether or propylene glycol butyl ether.
6. The method for producing 3-chlorobenzeneboronic acid according to claim 1, wherein: the method specifically comprises the following steps:
preparation of a Grignard reagent
Under the protection of nitrogen, adding magnesium strips, anhydrous tetrahydrofuran and iodine into a reaction container, heating until the tetrahydrofuran boils, starting to reflux, stopping heating, dropwise adding a mixed solution of m-chlorobromobenzene and tetrahydrofuran, and carrying out reflux reaction for 4-6 h to obtain a Grignard reagent solution;
synthesis of di, 3-chlorobenzene boric acid
Under the protection of nitrogen, dropwise adding the prepared Grignard reagent solution into a mixed solution of tetrahydrofuran and boric acid ester, keeping the reaction temperature at-35 to-45 ℃, continuously stirring and reacting after the Grignard reagent solution is completely added until all precipitates are dissolved, and then heating the reaction mixture to 0-4 ℃ in a cold water bath;
adding 10% sulfuric acid into the reaction mixture under stirring, standing for layering, separating organic layer, extracting water layer with ether solvent, mixing organic layers, drying with anhydrous sodium sulfate, and filtering;
and distilling the filtrate under reduced pressure, recovering the solvent, adding water, heating to 96-99 ℃, cooling to 55-65 ℃ at the speed of 0.5-20 ℃/h, preserving heat for 0.5-1.5 hours, cooling to 15-25 ℃ at the speed of 0.5-20 ℃/h, preserving heat for 0.5-1.5 hours, pulping and washing a filter cake with petroleum ether, filtering, and drying to obtain a finished product.
7. The method for producing 3-chlorobenzeneboronic acid according to claim 6, wherein: in the second step, the gradient cooling crystallization process is as follows: adding water into the filtrate, heating to 98 ℃, cooling to 60 ℃ at a speed of 0.5-20 ℃/h, preserving heat for 1 hour, cooling to 20 ℃ at a speed of 0.5-20 ℃/h, and preserving heat for 1 hour.
8. The method for producing 3-chlorobenzeneboronic acid according to claim 6, wherein: in the second step, the filter cake is beaten and washed at least twice by petroleum ether.
9. The 3-chlorobenzeneboronic acid prepared by the preparation method of 3-chlorobenzeneboronic acid as claimed in any one of claims 1 to 8, which is used as a medical intermediate for synthesizing the kovoxostat.
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| EP1314727A1 (en) * | 2001-11-23 | 2003-05-28 | Merial | Direct synthesis of quaternary phenanthridinium salts |
| CN111647011A (en) * | 2020-07-16 | 2020-09-11 | 宁夏中星显示材料有限公司 | Preparation method of monohalogenated phenylboronic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1314727A1 (en) * | 2001-11-23 | 2003-05-28 | Merial | Direct synthesis of quaternary phenanthridinium salts |
| CN111647011A (en) * | 2020-07-16 | 2020-09-11 | 宁夏中星显示材料有限公司 | Preparation method of monohalogenated phenylboronic acid |
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