KR20110045490A - Process For Preparing Aromatic boronic Acid - Google Patents
Process For Preparing Aromatic boronic Acid Download PDFInfo
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- KR20110045490A KR20110045490A KR1020090102095A KR20090102095A KR20110045490A KR 20110045490 A KR20110045490 A KR 20110045490A KR 1020090102095 A KR1020090102095 A KR 1020090102095A KR 20090102095 A KR20090102095 A KR 20090102095A KR 20110045490 A KR20110045490 A KR 20110045490A
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- boronic acid
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 12
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000006184 cosolvent Substances 0.000 claims abstract description 16
- -1 alkyl boronate Chemical compound 0.000 claims abstract description 11
- 239000000460 chlorine Substances 0.000 claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 7
- 150000004792 aryl magnesium halides Chemical class 0.000 claims abstract description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000004175 fluorobenzyl group Chemical group 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 20
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract 2
- 239000004327 boric acid Substances 0.000 abstract 2
- 229940127554 medical product Drugs 0.000 abstract 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 18
- 239000011777 magnesium Substances 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 238000010306 acid treatment Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 229910052749 magnesium Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000001543 aryl boronic acids Chemical class 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- APSMUYYLXZULMS-UHFFFAOYSA-N 2-bromonaphthalene Chemical compound C1=CC=CC2=CC(Br)=CC=C21 APSMUYYLXZULMS-UHFFFAOYSA-N 0.000 description 2
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 2
- AQZGPSLYZOOYQP-UHFFFAOYSA-N Diisoamyl ether Chemical compound CC(C)CCOCCC(C)C AQZGPSLYZOOYQP-UHFFFAOYSA-N 0.000 description 2
- AYDIZIVBZWNEGJ-UHFFFAOYSA-N OBO.CC1=CC=CC=C1 Chemical compound OBO.CC1=CC=CC=C1 AYDIZIVBZWNEGJ-UHFFFAOYSA-N 0.000 description 2
- DCLBYJRXBUZJQP-UHFFFAOYSA-N OBO.FC1=CC=CC=C1 Chemical compound OBO.FC1=CC=CC=C1 DCLBYJRXBUZJQP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012776 electronic material Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 1
- WJIFKOVZNJTSGO-UHFFFAOYSA-N 1-bromo-3-methylbenzene Chemical compound CC1=CC=CC(Br)=C1 WJIFKOVZNJTSGO-UHFFFAOYSA-N 0.000 description 1
- BPIUIOXAFBGMNB-UHFFFAOYSA-N 1-hexoxyhexane Chemical compound CCCCCCOCCCCCC BPIUIOXAFBGMNB-UHFFFAOYSA-N 0.000 description 1
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HHBZZTKMMLDNDN-UHFFFAOYSA-N 2-butan-2-yloxybutane Chemical compound CCC(C)OC(C)CC HHBZZTKMMLDNDN-UHFFFAOYSA-N 0.000 description 1
- BUWXUSLQPDDDSD-UHFFFAOYSA-N 2-methyl-2-(2-methylbutan-2-yloxy)butane Chemical compound CCC(C)(C)OC(C)(C)CC BUWXUSLQPDDDSD-UHFFFAOYSA-N 0.000 description 1
- UVEFRWMGQRNNDB-UHFFFAOYSA-N 2-pentan-2-yloxypentane Chemical compound CCCC(C)OC(C)CCC UVEFRWMGQRNNDB-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- BYQADQLDVPAGSR-UHFFFAOYSA-N toluene;hydrobromide Chemical compound Br.CC1=CC=CC=C1 BYQADQLDVPAGSR-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
Description
The present invention relates to a method for producing an aromatic boronic acid compound, and more specifically, to an aromatic boronic acid (or aryl boronic acid, aryl) by reacting an aryl magnesium halide and an alkyl boronate at a constant temperature in the presence of a co-solvent Boronic acid).
Representative among aromatic boronic acid compounds are phenyl boronic acid (PBA), naphthalene boronic acid (NBA), fluorobenzene boronic acid (FBA), toluene boronic acid (TBA). The basic synthesis scheme of the aromatic boronic acid compound is as shown in the following figure to activate the aryl halide with a metal (Mg, Li), react with a boron compound such as trialkyl borate and boron, and then aryl boronic acid by quenching (Synthesis Organic Synthesis, Coll. Vol. IV, p68, John Wiley & Sons (1963)).
Scheme 1 Synthesis Scheme of Representative Aryl Boronic Acid
(OTF: trifluoromethanesulfonyloxy)
This method uses tetrahydrofuran (THF), which is expensive and dangerous to handle, and requires a reaction at cryogenic temperatures of -78 ° C as a reaction temperature condition to obtain an appropriate yield, and also to obtain magnesium (Mg) metal, Hazardous reagents such as lithium (Li) metals are used and therefore are not suitable for industrial methods due to the risk of fire and explosion due to hydrogen generation.
As a second synthesis method, a synthesis method using a noble metal catalyst such as palladium and a diborane compound such as bis (pinacolato) diborane, as shown in Scheme 2, has been reported to be developed in a laboratory (Ref. J). Org.Chem. 60, 7508-7510 (1995)).
Scheme 2
However, the above method is also a low-temperature reaction, but difficult to recover expensive noble metal catalyst, and the reaction proceeds only by using a ligand such as phosphorus (P) -based dichlorobis (diphenylphosphino perusenir) (DPPF) It is still difficult to apply industrially.
Therefore, in order to develop a synthetic method that can be economically and industrially applied, the conditions of the reaction solvent, reaction temperature, and acid treatment method through preliminary experiments of phenylboronic acid are changed to find the optimum operating conditions and industrial use. The possible methods were found and the following invention was completed.
In the conventional method, that is, the conventional classical Grignard method, a high yield is obtained only by synthesizing at a very low temperature, for example, a temperature of about -70 ° C. Therefore, the operating conditions of about -70 ° C are industrially applied. There was a problem that this was difficult. In order to industrially manufacture by such a conventional method, it is preferable to manufacture at least at -20 ° C to around 0 ° C to room temperature. However, there have been disadvantages in that the yield is low and many impurities are generated in this temperature range.
Accordingly, the present invention is to provide a method for producing an aromatic boronic acid by using a specific co-solvent to obtain a result of improved yield in the industrially applicable temperature range (-40 ~ 0 ℃ range) .
First, the present inventors synthesized Ph-MgBr by adding Mg, Et 2 O (diethyl ether) or THF to reflux to bromobenzene to react with trimethyl boride, and then reacted with 10% H 2 SO 4 or saturated NH 4. In the process of quenching with Cl or 2N HCl to obtain the desired phenylboronic acid, it is experimentally synthesized and analyzed by TLC, HPLC, 13 C NMR, 1 H NMR, IR, etc. It was intended to invent the method. In addition, the possibility of producing by-products other than the product in the process of synthesizing the possibility was examined through the following mechanism.
1) Mechanism
The present inventors believe that the reaction factors that can affect the yield of the product (phenylboronic acid) through the above mechanism are (1) solvent, (2) reaction temperature, (3) quenching method, (4) crystallization temperature. In consideration of each of these effects through various experiments.
(1) Influence of solvent
Using the same solvent, acid treatment method, and crystallization temperature and lowering the reaction temperature from room temperature to -70 ° C, the experiment showed that the lower the reaction temperature, the better the yield. Based on these results, experiments were carried out to investigate the effect of solvent on the reaction at low temperatures. The solvent was changed from THF to Et 2 O, the reaction temperature was −60 ° C., the crystallization temperature was room temperature, and the acid treatment method was the same as 10% H 2 SO 4 . As a result, it was found that the solvent was Et 2 O and the reaction temperature was -60 ° C. to -70 ° C., whereby the product was obtained with better yield. However, the above experiments did not yield high yields.
(2) influence of crystallization temperature
Subsequently, other factors as shown in Robert M. Washburn; Ernest Levenes; Charles F. Albright; Franklin A. Billig. Org.Synth . Coll., 1963, 4, 68 ; 1959, 39, 3; Among them, the lower the crystallization temperature was expected to obtain a higher yield was tested by changing the crystallization temperature.
Et 2 O is used as the solvent, the reaction temperature is -60 ° C., and the acid treatment method is the same as that of 10% H 2 SO 4 , and the crystallization temperature is lowered from room temperature to 0 ° C .. It can be synthesized in a higher yield than the literature 1, the lower the crystallization temperature was synthesized in a higher yield.
(3) Effect of acid quenching method
After obtaining the above results, it will be described how the acid treatment method may affect the yield of the reaction. THF was used as the solvent, the reaction temperature and the crystallization temperature were the same at room temperature, and the acid treatment method was changed from 10% H 2 SO 4 to saturated NH 4 Cl.
Higher yields were obtained when saturated NH 4 Cl was used than when quenching was used with 10% H 2 SO 4 . Better yields were obtained than the yields of prior art 2 (Kazuaki Ishihara; Suguru Ohara; Hisashi Yamamoto, Org. Synth. Coll., 2004 , 10 , 80; 2002, 79, 176), tested under the same conditions. This shows that it is better to use saturated NH 4 Cl than to use 10% H 2 SO 4 in the acid quenching method.
In addition, as the solvent, THF was used, the reaction temperature and the crystallization temperature were kept at room temperature, and the acid treatment method was changed to 2N HCl. This experiment yielded better yields than that of saturated NH 4 Cl. In other words, it was found that the acid treatment method is better to use saturated NH 4 Cl than 10% H 2 SO 4 and 2N HCl rather than saturated NH 4 Cl.
(4) Influence of use of cosolvent
On the other hand, the inventors of the present invention using Et 2 O as the solvent, the reaction temperature is 0 ℃ ~ room temperature, the acid treatment using 2N HCl, the crystallization temperature of the reaction at room temperature as a result, the product of about 78% It was possible to synthesize in a yield, when using a co-solvent in the same conditions was able to obtain a yield of 84% at room temperature, 90% yield at -40 ℃.
Based on the results of the above various experiments, the present invention was selected as the optimum conditions that can be used industrially in the present invention by using a solvent as a co-solvent, a reaction temperature of -40 ° C. to room temperature, and an acid treatment solution as 2N HCl. As in the example, the synthesis process of PBA, NBA, FBA, TBA of a certain scale was carried out.
The present invention can synthesize an aromatic boron compound useful as a base material such as electronic materials or pharmaceuticals through an optimal synthesis method within the range of -40 ℃ to room temperature using a cosolvent.
As a first embodiment of the present invention, an aromatic boronic acid is reacted by reacting an aryl magnesium halide (Formula 1) and an alkyl boronate (Formula 2) in the presence of a co-solvent at a constant temperature, as shown in the following scheme. To prepare the formula (3):
Ar-MgX (Formula 1) + B (OR) 3 (Formula 2) → Ar-B (OH) 2 (Formula 3)
In this formula,
Ar is an aromatic phenyl group, naphthyl group, fluorobenzyl group or toluene group,
X is a halogen group such as chlorine or bromine,
In a second aspect of the invention, the cosolvent of the invention is based on any one of THF (tetrahydrofuran), methyl tetrahydrofuran and ether, with toluene, xylene, monochlorobenzene (MCB) and ortho-dichloro It is preferable that any one of benzene (ODCB) is selected and used jointly as a cosolvent.
Moreover, this invention is 3rd aspect, It is preferable to select the temperature of this invention in the range of -40-0 degreeC. If the reaction temperature is lower than -40 ℃ is not industrially preferable, if it exceeds 0 ℃ there is a problem that the yield and the like falls.
The reagents used in the synthesis of the present invention may be used as long as the reagents do not depart from the object of the present invention. Reagent phenylmagnesium bromide (Aldrich, 1.0 M solution in tetrahydrofuran) used in the synthesis of the present invention, trimethyl borate (TCI), 1-bromo-3-fluorobenzene (Aldrich, 99 +%), 2-bro Monaphthalene (Aldrich, 97%), bromobenzene (Sigma-Aldrich, 99%), 3-bromotoluene (Aldrich, 98%) were mainly purchased from Aldrich and used without purification. All solvents used were distilled off by the usual purification methods. Thin-Layer Chromatography (TLC) used silica gel 60 F254 (Merck 25). Ethyl acetate and hexane (manufactured by Daejung Chemical Co., Ltd.) were used as the eluent for TLC.
Generally, a cosolvent is a generic term for solvents used together in a specific reaction, taking into account specific reaction steps and costs. For example, co-solvents use two or more solvents, as melting a rubber with only toluene takes 12 hours, whereas adding a small amount of hexane, ethyl acetate, etc. reduces the dissolution time. It is also used to further increase the desired performance.
In the present invention, as described above, when using a co-solvent in the process of selecting the optimum conditions that can be industrially available on the basis of various experimental results for the synthesis of aryl boronic acid, the reaction temperature by chance even at -40 to 0 ℃ The present invention has been completed based on the fact that the product can be obtained in the desired yield.
As the basic solvent used in the present invention, any one of THF (tetrahydrofuran), methyl tetrahydrofuran and ether can be used as used in the prior art. Here, as the ether solvent, THF, diethyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, di-n-pentyl ether, methylcyclopentyl ether, methylcyclohexyl ether, di-n -Butyl ether, di-sec-butyl ether, diisopentyl ether, di-sec-pentyl ether, di-t-amyl ether, di-n-hexyl ether and the like.
In addition, as an auxiliary solvent to be used with the basic solvent of the present invention, any one of toluene, xylene, monochlorobenzene (MCB) and ortho-dichlorobenzene (ODCB) may be selected and used.
Product structure analysis and purity measurement
Used for structural analysis of the product of the present invention 1 H-NMR and 13 C NMR were measured using 400 MHz FT-NMR (Bruker). Chemical shifts (d) are expressed in parts per million (ppm) relative to tetramethylsilane and coupling constants ( J values) are expressed in hertz. FT-IR was measured using VERTEX 70 (Bruker) in the laboratory.
The following examples specifically illustrate the process of directly preparing the aryl magnesium halide required in each embodiment starting from Mg to activate it, but by omitting the entire process, the allyl magnesium halide reagent can be directly purchased to directly alkyl. Reaction with boronate may produce the desired aryl boronic acid. In addition, the following examples and experimental procedures are provided to better understand the present invention, and do not limit the scope of the present invention as defined in the claims.
Example 1 Synthesis of Phenyl Boronic Acid (PBA)
1) Experimental method
Mg 15.5g (0.64 mol) was added to a 1 L three-necked flask, and the internal air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C. while stirring for 1 hr using a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.64 mol) of bromo benzene is dissolved in 300 ml of THF and slowly added over 1.5 hr.
100 g (0.96 mol) of trimethyl borate was added to a separate 1 L three-necked flask, and 150 ml of THF / toluene was added and stirred at -20 to 0 ° C. Here, phenylmagnesium bromide prepared above was slowly added dropwise (maintained at -20 to 0 ° C.) and stirred at 0 ° C. for 5 h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H 2 O, dry over MgSO 4 , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to determine the yield, purity (by LC).
2) Experimental result
The test procedure was carried out at the reaction temperature of 0 ℃, -10 ℃, -20 ℃, respectively, the average yield was 87%, it was possible to obtain a white solid with a purity of 99.0%. 1 H NMR (400 MHz, CDCl 3 ); δ 8.26 (d, 1H, J = 6.7 Hz, Ar-H), 7.74 (d, 1H, J = 6.8 Hz, Ar-H), 7.61 (t, 1H, J = 6.7 Hz, Ar-H), 7.43-7.54 (m, 1H, Ar-H), 7.41 (t, 1H, J = 6.8 Hz, Ar-H) ppm.
Example 2 Synthesis of Naphthalene Boronic Acid (NBA)
1) Experimental method
Mg 12.2g (0.50 mol) was added to a 1L three-necked flask, and the inside air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C while stirring for 1hr with a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.48 mol) of 2-bromonaphthalene is dissolved in 300 ml of THF and slowly added over 1.5 hr.
Into a separate 1 L three-necked flask, 74.8 g (0.72 mol) of trimethyl borate was added, and 150 ml of THF / toluene was added and stirred at -40 to -20 ° C. Here, phenylmagnesium bromide prepared above was slowly added dropwise (internal temperature maintained at -40 to -20 ° C) and stirred at 0 ° C for 5h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H 2 O, dry over MgSO 4 , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).
2) Experimental results
The test procedure was carried out at the reaction temperature of -20 ℃, -20 ℃, -40 ℃, respectively, the average yield was 83%, it was able to obtain a white solid with a purity of 99.3%. 1 H NMR (400 MHz, DMSO); δ 9.11 (d, 1H, J = 6.7 Hz, Ar-H), 8.38 (d, 1H, J = 7.0 Hz, Ar-H), 7.92 (d, 1H, J = 7.9 Hz, Ar-H), 7.90 (t, 1H, J = 7.3 Hz, Ar-H), 7.88 (t, 1H, J = 6.4 Hz, Ar-H), 7.54-7.32 (m, 1H, Ar-H), 7.30 (dt, 1H, J HF = 8.3 Hz, J = 2.6 Hz, Ar-H) ppm.
Example 3 Synthesis of Fluorobenzene Boronic Acid (FBA)
1) Experimental method
Mg 14.1 g (0.58 mol) was added to a 1 L three-necked flask, and the internal air was removed by vacuum, and washed three times with nitrogen. Then, the temperature was raised to 200 ° C. while stirring for 1 hr using a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.57 mol) of 3-fluorobenzene was dissolved in 300 ml of THF, and then slowly added over 1.5 hours.
88.3 g (0.85 mol) of trimethyl borate was added to a separate 1 L three-neck flask, and 150 ml of THF / toluene was added and stirred at -30 to -40 ° C. The phenylmagnesium bromide prepared above is slowly added dropwise (maintained at -30 ~ -40 ℃) and stirred for 5 h at 0 ℃. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H 2 O, dry over MgSO 4 , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).
2) Experimental results
The test procedure was carried out at the reaction temperature of -30 ℃, -30 ℃, -40 ℃ respectively, the average yield was 81.3%, it was able to obtain a white solid of 99.0% purity. 1 H NMR (400 MHz, CDCl 3 ); δ 7.99 (d, 1H, J HF = 7.3 Hz, Ar-H), 7.86 (dd, 1H, J HF = 8.9 Hz, J = 2.6 Hz, Ar-H), 7.48-7.53 (m, 1H, Ar -H), 7.30 (dt, 1H, J HF = 8.3 Hz, J = 2.6 Hz, Ar-H) ppm.
Example 4 Synthesis of Toluene Boronic Acid (TBA)
1) Experiment Method
Mg 14.3g (0.59 mol) was added to a 1L three-necked flask, and the internal air was removed by vacuum. After washing three times with nitrogen, the temperature was raised to 200 ° C. while stirring for 1hr with a magnetic stirrer to activate magnesium. After the temperature was lowered below 80 ° C., 300 ml of dry THF / toluene and 1 piece of iodine were added thereto, followed by stirring at reflux for 1 hr. In a dropping funnel, 100 g (0.58 mol) of 3-methylbenzene bromide is dissolved in 300 ml of THF, and slowly added over 1.5 hr.
90.4 g (0.87 mol) of trimethyl borate was added to a separate 1 L three-necked flask, and 150 ml of THF / toluene was added and stirred at -40 to -20 ° C. The Grignard reagent (magnesium organometallic) prepared above was slowly added dropwise (maintained at -40 to -20 ° C) and stirred at 0 ° C for 5 h. The progress of the reaction is checked via TLC. After the reaction was completed, 200 ml of 2N HCl was added at 0 ° C., stirred for 1 h, and then taken out to room temperature. Extract with EA / H 2 O, dry over MgSO 4 , filter and distillation under reduced pressure. The obtained solid is recrystallized under EA / hexane conditions and filtered to measure the yield and purity (by LC).
2) Experiment result
The test procedure was carried out at the reaction temperature of -20 ℃, -20 ℃, -40 ℃ respectively, the average yield was 82%, it was able to obtain a white solid of 99.0% purity. 1 H NMR (400 MHz, CDCl 3 ); δ 8.05 (t, 1H, J = 5.6 Hz, Ar-H), 8.05 (s, 1H, Ar-H), 7.41 (t, 2H, J = 5.6 Hz, Ar-H), 2.47 (s, 3H , toluene CH 3 ) ppm.
In consideration of the above Examples 1 to 4 as a whole, as a result of each performed at -40 to 0 ℃, the aromatic boronic acid to be synthesized in the present invention was each obtained an average yield of 81.3% to 87%. Through these examples, the present invention confirms that the desired aryl boronic acid PBA, NBA, FBA, TBA can be synthesized in a desired yield by using a cosolvent in an industrially available temperature range, that is, -40 to 0 ° C. Could.
The aromatic boronic acid compound obtained in the present invention will be usefully used as a base material for electronic materials or pharmaceuticals.
Those skilled in the art will appreciate that various changes and / or modifications may be made through the above detailed description and examples, and that such changes and / or modifications may be made without departing from the spirit of the invention. something to do. Accordingly, the appended claims should be construed as including all changes and / or modifications within the spirit and scope of the invention.
Claims (3)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311587A (en) * | 2013-11-12 | 2015-01-28 | 广州康瑞泰药业有限公司 | Process for producing fluorine-containing phenylboronic acid |
| CN113845537A (en) * | 2021-09-13 | 2021-12-28 | 金仓(上海)医药生物科技有限公司 | 2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-boric acid and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311587A (en) * | 2013-11-12 | 2015-01-28 | 广州康瑞泰药业有限公司 | Process for producing fluorine-containing phenylboronic acid |
| CN113845537A (en) * | 2021-09-13 | 2021-12-28 | 金仓(上海)医药生物科技有限公司 | 2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-boric acid and preparation method thereof |
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