CN106565761A - Preparing technology for 4-carboxyphenylboronic acid - Google Patents
Preparing technology for 4-carboxyphenylboronic acid Download PDFInfo
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- CN106565761A CN106565761A CN201611003540.0A CN201611003540A CN106565761A CN 106565761 A CN106565761 A CN 106565761A CN 201611003540 A CN201611003540 A CN 201611003540A CN 106565761 A CN106565761 A CN 106565761A
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- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000005516 engineering process Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- -1 triisopropyl borate ester Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000005885 boration reaction Methods 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 abstract description 3
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 abstract 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract 1
- 229910052796 boron Inorganic materials 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 24
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000005406 washing Methods 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- KWNPRVWFJOSGMZ-UHFFFAOYSA-N 2-boronobenzoic acid Chemical compound OB(O)C1=CC=CC=C1C(O)=O KWNPRVWFJOSGMZ-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical class COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical class COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 description 4
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 235000010338 boric acid Nutrition 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ZZYYOHPHSYCHQG-UHFFFAOYSA-N 2-bromo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(Br)=C1 ZZYYOHPHSYCHQG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical class OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 1
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- 229940118364 Bcr-Abl inhibitor Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect 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
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- SWGQITQOBPXVRC-UHFFFAOYSA-N methyl 2-bromobenzoate Chemical compound COC(=O)C1=CC=CC=C1Br SWGQITQOBPXVRC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparing technology for 4-carboxyphenylboronic acid. Iodobenzoic acid serves as raw materials, the target product 4-carboxyphenylboronic acid is obtained through the esterification reaction, the boron acidification reaction and the hydrolysis reaction, and the total yield can reach 88.7%. According to the process route, raw materials are cheap and easy to obtain, postprocessing is simple, convenient and easy to implement, the yield is high, and industrial application is easy.
Description
Technical field
The present invention relates to a kind of preparation technology of 4- Carboxybenzeneboronic acids, belongs to the technical field of chemical intermediate.
Background technology
4- Carboxybenzeneboronic acids are a kind of very important chemical intermediates, are widely used in medicine and other fields.Boric acid class
Compound can occur Suzuki reactions with chlorine, bromine or iodine for aromatic hydrocarbons and alkene, and so as to connect various groups, downstream product is very
It is abundant.Can be used to prepare the antitumor inhibitor such as Bcr-Abl inhibitor (referring to patent CN104262244).
The method of CN104262263, CN104262244 report is with parabromotoluene as raw material, and the reaction time is long, and operation is multiple
It is miscellaneous, yield relatively low (respectively 44%, 57%).
The method of CN103724366 reports is with parabromobenzoic acid as raw material, although avoid waterless operation, but yield is only
59%, it is not ideal enough.
Although the method yield of WO2007121805 reports is preferably, with expensive 4- cyanophenylboronic acids, 4- amino first
Acyl phenyl boric acid is raw material, and production cost is high.
The method of US2002037905 reports, as raw material, by n-BuLi boric acid on iodine is pulled out with to iodotoluene, then by benzene
Methyl oxidation on ring is into carboxylic acid 4- Carboxybenzeneboronic acids, and impurity is more, and post processing is difficult and yield is relatively low.
In sum, reported that the presence yield of the synthetic method with regard to 4- Carboxybenzeneboronic acids is relatively low at present (to be less than
60%), reaction time length or the problems such as expensive raw material price, is unfavorable for industrialized production.
The content of the invention
The technical problem to be solved in the present invention is：A kind of preparation technology of 4- Carboxybenzeneboronic acids is provided, to solve existing skill
Art prepare 4- Carboxybenzeneboronic acids when, yield is relatively low, reaction time length, expensive raw material price the problems such as.
Technical scheme：A kind of preparation technology of 4- Carboxybenzeneboronic acids, comprises the steps of：With 4-Iodobenzoic acid
For raw material, Jing esterifications obtain compounds of formula I；The reaction of compounds of formula I Jing boration obtains the chemical combination of formula II
Thing；Compounds of formula II Jing hydrolysis obtains target product 4- Carboxybenzeneboronic acids,
Intermediate in described process route is compounds of formula I, and wherein R is：Methyl or ethyl.
Intermediate in described process route is compounds of formula II, and wherein R is：Methyl or ethyl.
The reagent that described (1) step esterification is used is：Methyl alcohol or ethanol；Dehydrating agent is：The concentrated sulfuric acid；Reaction temperature
For：Backflow；Reaction time is：5～6h.
4-Iodobenzoic acid is with the mol ratio of the concentrated sulfuric acid in described (1) step esterification：1:1.1～2.
Described (2) step boration reacts agents useful for same：Trimethylborate, n-butyl boronate or the isopropyl of boric acid three
Ester；Solvent is：Anhydrous tetrahydro furan；Catalyst is：N-BuLi or isopropyl magnesium bromide；Reaction temperature is：-78℃；Reaction
Time is：0.5～1h.
The compound and trimethylborate, tri-n-butyl borate, boric acid of described (2) step boration reaction formula of I
The mol ratio of three isopropyl esters is：1:1.2～3；Compounds of formula I is with the mol ratio of n-BuLi or isopropyl magnesium bromide：
1:1.1～2.
The alkali that described (3) step hydrolysis is used is：Potassium hydroxide aqueous solution or sodium hydrate aqueous solution；Solvent
For：Tetrahydrofuran；Reaction temperature is：Backflow；Reaction time is：2～4h.
The compound of described (3) step hydrolysis formula of II is with the mol ratio of alkali：1:2～4.
Beneficial effects of the present invention：By the present invention in that be raw material with 4-Iodobenzoic acid cheap and easy to get, Jing three-step reactions
Target product 4- Carboxybenzeneboronic acids are obtained, total recovery is up to 88.7%.The process route raw material is cheap and easily-available, intermediate and product
Just can purify through steps such as extraction, reduction vaporization, beating, suction filtrations, the post processing of whole piece route is not used the inconvenience such as column chromatography
Industrialized method, it is simple and easy to do.
Specific embodiment
Embodiment 1
A.4- the synthesis of iodo-benzoic acid methyl esters
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into methyl alcohol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (8.7g, 88.7mmol), back flow reaction 5h.Reaction is finished, evaporated under reduced pressure, and residue water (20mL × 2) is washed
Wash, be vacuum dried, obtain 4- iodo-benzoic acid methyl esters 20.1g, yield is 95.1%.
B.4- the synthesis of methoxycarbonyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo-benzoic acid methyl esters (20.1g, 76.7mmol) is dissolved in into anhydrous THF (200.0mL),
Triisopropyl borate ester (18.0g, 95.9mmol) is added, -78 DEG C are cooled to, n-BuLi (6.1g, 95.9mmol) is added dropwise, kept
Thermotonus 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, ethyl acetate
(100.0mL × 3) extract, and merge organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure molten
Agent, residue is beaten with n-hexane, and suction filtration obtains final product 4- methoxycarbonyl group phenyl boric acid 13.1g, and yield is 94.8%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- methoxycarbonyl group phenyl boric acids (13.1g, 72.7mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq NaOH (6.5g, 162.1mmol), back flow reaction 2h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxyls
Phenyl boric acid 11.6g.Yield 96.0%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 2
A.4- the synthesis of iodo ethyl benzoate
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into ethanol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (8.7g, 88.7mmol), back flow reaction 5h.Reaction is finished, evaporated under reduced pressure, and residue water (20mL × 2) is washed
Wash, be vacuum dried, obtain 4- iodo ethyl benzoate 20.9g, yield is 94.0%.
B.4- the synthesis of carbethoxyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo ethyl benzoates (20.9g, 75.8mmol) are dissolved in into anhydrous THF (300.0mL),
Triisopropyl borate ester (42.8g, 227.4mmol) is added, -78 DEG C are cooled to, n-BuLi (9.7g, 151.6mmol) is added dropwise, protected
Hold thermotonus 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, acetic acid second
Ester (150.0mL × 3) is extracted, and merges organic phase, and saturated aqueous common salt (100mL × 1) washing, anhydrous sodium sulfate drying, decompression is steamed
Except solvent, residue are beaten with n-hexane, suction filtration obtains final product 4- carbethoxyl group phenyl boric acid 13.5g, and yield is 92.0%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- carbethoxyl group phenyl boric acids (13.5g, 69.7mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq NaOH (6.1g, 153.4mmol), back flow reaction 3h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxyls
Phenyl boric acid 11.0g.Yield 95.2%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 3
A.4- the synthesis of iodo-benzoic acid methyl esters
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into methyl alcohol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (15.8g, 161.3mmol), back flow reaction 6h.Reaction is finished, evaporated under reduced pressure, and residue is with water (20mL × 2)
Washing, vacuum drying, obtains 4- iodo-benzoic acid methyl esters 20.4g, and yield is 96.5%.
B.4- the synthesis of methoxycarbonyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo-benzoic acid methyl esters (20.4g, 77.8mmol) is dissolved in into anhydrous THF (200.0mL),
Tri-n-butyl borate (21.5g, 93.4mmol) is added, -78 DEG C are cooled to, n-BuLi (5.5g, 85.6mmol) is added dropwise, kept
Thermotonus 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, ethyl acetate
(100.0mL × 3) extract, and merge organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure molten
Agent, residue is beaten with n-hexane, and suction filtration obtains final product 4- methoxycarbonyl group phenyl boric acid 12.7g, and yield is 91.0%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- methoxycarbonyl group phenyl boric acids (12.7g, 70.8mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq NaOH (7.1g, 177.0mmol), back flow reaction 3h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxyls
Phenyl boric acid 11.3g.Yield 96.5%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 4
A.4- the synthesis of iodo-benzoic acid methyl esters
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into methyl alcohol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (11.9g, 121.0mmol), back flow reaction 6h.Reaction is finished, evaporated under reduced pressure, and residue is with water (20mL × 2)
Washing, vacuum drying, obtains 4- iodo-benzoic acid methyl esters 20.3g, and yield is 96.0%.
B.4- the synthesis of methoxycarbonyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo-benzoic acid methyl esters (20.3g, 77.4mmol) is dissolved in into anhydrous THF (200.0mL),
Trimethylborate (16.1g, 154.8mmol) is added, -78 DEG C are cooled to, n-BuLi (7.4g, 116.1mmol) is added dropwise, kept
Thermotonus 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, ethyl acetate
(100.0mL × 3) extract, and merge organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure molten
Agent, residue is beaten with n-hexane, and suction filtration obtains final product 4- methoxycarbonyl group phenyl boric acid 13.2g, and yield is 94.5%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- methoxycarbonyl group phenyl boric acids (13.2g, 73.2mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq potassium hydroxide (8.2g, 163.1mmol), back flow reaction 2h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxyls
Phenyl boric acid 11.4g.Yield 94.2%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 5
A.4- the synthesis of iodo ethyl benzoate
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into ethanol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (8.7g, 88.7mmol), back flow reaction 5.5h.Reaction is finished, evaporated under reduced pressure, and residue is with water (20mL × 2)
Washing, vacuum drying, obtains 4- iodo ethyl benzoate 21.3g, and yield is 95.5%.
B.4- the synthesis of carbethoxyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo ethyl benzoates (21.3g, 77.0mmol) are dissolved in into anhydrous THF (200.0mL),
Tri-n-butyl borate (26.6g, 115.5mmol) is added, -78 DEG C are cooled to, n-BuLi (6.9g, 107.8mmol) is added dropwise, protected
Hold thermotonus 1h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, ethyl acetate
(100.0mL × 3) extract, and merge organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure molten
Agent, residue is beaten with n-hexane, and suction filtration obtains final product 4- carbethoxyl group phenyl boric acid 14.0g, and yield is 93.4%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- carbethoxyl group phenyl boric acids (14.0g, 71.9mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq potassium hydroxide (7.2g, 143.9mmol), back flow reaction 2h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxyls
Phenyl boric acid 11.1g.Yield 92.6%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 6
A.4- the synthesis of methyl-bromobenzoate
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into methyl alcohol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (9.5g, 96.8mmol), back flow reaction 5h.Reaction is finished, evaporated under reduced pressure, and residue water (20mL × 2) is washed
Wash, be vacuum dried, obtain 4- methyl-bromobenzoate 20.2g, yield is 95.7%.
B.4- the synthesis of methoxycarbonyl group phenyl boric acid
In 500mL there-necked flasks, 4- methyl-bromobenzoates (20.2g, 77.2mmol) are dissolved in into anhydrous THF (200.0mL),
Triisopropyl borate ester (18.9g, 100.3mmol) is added, -78 DEG C are cooled to, n-BuLi (6.8g, 96.5mmol) is added dropwise, protected
Hold thermotonus 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, acetic acid second
Ester (100.0mL × 3) is extracted, and merges organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure
Solvent, residue is beaten with n-hexane, and suction filtration obtains final product 4- methoxycarbonyl group phenyl boric acid 13.3g, and yield is 95.5%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 100mL two-mouth bottles, 4- methoxycarbonyl group phenyl boric acids (13.3g, 221.1mmol) is dissolved in into THF (200mL), plus
Enter 2.5mol/L aq potassium hydroxide (8.1g, 162.2mmol), back flow reaction 4h.Reaction is finished, and reactant liquor is poured in frozen water,
Ethyl acetate (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted,
Merge organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxylics
Base phenyl boric acid 11.1g.Yield 92.6%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 7
A.4- the synthesis of iodo ethyl benzoate
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into ethanol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (8.7g, 88.7mmol), back flow reaction 5h.Reaction is finished, evaporated under reduced pressure, and residue water (20mL × 2) is washed
Wash, be vacuum dried, obtain 4- iodo ethyl benzoate 21.1g, yield is 94.7%.
B.4- the synthesis of carbethoxyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo ethyl benzoates (21.1g, 76.4mmol) are dissolved in into anhydrous THF (200.0mL),
Tri-n-butyl borate (26.4g, 114.5mmol) is added, -78 DEG C are cooled to, n-BuLi (6.9g, 106.9mmol) is added dropwise, protected
Hold thermotonus 1h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L adjusts pH value to 1, ethyl acetate
(100.0mL × 3) extract, and merge organic phase, and saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying is removed under reduced pressure molten
Agent, residue is beaten with n-hexane, and suction filtration obtains final product 4- carbethoxyl group phenyl boric acid 14.0g, and yield is 94.4%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- carbethoxyl group phenyl boric acids (14.0g, 72.1mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq potassium hydroxide (8.13g, 162.2mmol), back flow reaction 2h.Reaction is finished, and reactant liquor is poured in frozen water,
Ethyl acetate (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted,
Merge organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains target product 4- carboxylics
Base phenyl boric acid 11.1g.Yield 92.6%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Embodiment 8
A.4- the synthesis of iodo-benzoic acid methyl esters
In 250mL there-necked flasks, 4-Iodobenzoic acid (20.0g, 80.6mmol) is dissolved in into methyl alcohol (100.0mL), it is slow to add
Enter 98% concentrated sulfuric acid (15.8g, 161.3mmol), back flow reaction 5h.Reaction is finished, evaporated under reduced pressure, and residue is with water (20mL × 2)
Washing, vacuum drying, obtains 4- iodo-benzoic acid methyl esters 20.0g, and yield is 94.6%.
B.4- the synthesis of methoxycarbonyl group phenyl boric acid
In 500mL there-necked flasks, 4- iodo-benzoic acid methyl esters (20.0g, 76.3mmol) is dissolved in into anhydrous THF (200.0mL),
Add triisopropyl borate ester (21.5g, 114.4mmol), be cooled to -78 DEG C, be added dropwise isopropyl magnesium bromide (15.7g,
106.8mmol), keeping temperature reaction 0.5h.Reaction is finished, and saturated aqueous ammonium chloride is quenched reaction, and the hydrochloric acid of 1mol/L is adjusted
To 1, ethyl acetate (100.0mL × 3) is extracted pH value, merges organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous slufuric acid
Sodium is dried, and removes solvent under reduced pressure, and residue is beaten with n-hexane, and suction filtration obtains final product 4- methoxycarbonyl group phenyl boric acid 12.9g, and yield is
93.6%.
C.4- the synthesis of Carboxybenzeneboronic acid
In 500mL two-mouth bottles, 4- methoxycarbonyl group phenyl boric acids (12.9g, 71.4mmol) is dissolved in into THF (200mL), is added
2.5mol/L aq potassium hydroxide (8.1g, 160.7mmol), back flow reaction 2h.Reaction is finished, and reactant liquor is poured in frozen water, second
Acetoacetic ester (20.0mL × 2) carries miscellaneous, 1mol/L hydrochloric acid solutions water transfer layer pH value to 1, and ethyl acetate (100.0mL × 3) is extracted, and closes
And organic phase, saturated aqueous common salt (60mL × 1) washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, obtains target product 4- carboxyls
Phenyl boric acid 10.9g.Yield 91.8%.
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H).
Claims (7)
1. a kind of preparation technology of 4- Carboxybenzeneboronic acids, it is characterised in that：Comprise the steps of：With 4-Iodobenzoic acid as raw material,
Jing esterifications obtain compounds of formula I；The reaction of compounds of formula I Jing boration obtains compounds of formula II；Formula
The compound Jing hydrolysis of II obtains target product 4- Carboxybenzeneboronic acids,
2. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 1, it is characterised in that：In in process route
Mesosome is compounds of formula I, and wherein R is：Methyl or ethyl.
3. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 1, it is characterised in that：In in process route
Mesosome is compounds of formula II, and wherein R is：Methyl or ethyl.
4. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 1, it is characterised in that：Described (1) step
The reagent that esterification is used is：Methyl alcohol or ethanol；Dehydrating agent is：The concentrated sulfuric acid；Reaction temperature is：Backflow.
5. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 1, it is characterised in that：Described (2) step
Boration reacts agents useful for same：Trimethylborate, n-butyl boronate or triisopropyl borate ester；Solvent is：Anhydrous tetrahydro furan；
Catalyst is：N-BuLi or isopropyl magnesium bromide；Reaction temperature is：-78℃.
6. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 5, it is characterised in that：Described (2) step
Boration reacts the compound of formula of I：1:
1.2～3；Compounds of formula I is with the mol ratio of n-BuLi or isopropyl magnesium bromide：1:1.1～2.
7. the preparation technology of a kind of 4- Carboxybenzeneboronic acids according to claim 1, it is characterised in that：Described (3) step
The alkali that hydrolysis is used is：Potassium hydroxide aqueous solution or sodium hydrate aqueous solution；Solvent is：Tetrahydrofuran；Reaction temperature is：
Backflow.
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