CN108409767A - A kind of preparation method of heterocycle biphenylboronic acid - Google Patents
A kind of preparation method of heterocycle biphenylboronic acid Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 19
- XPEIJWZLPWNNOK-UHFFFAOYSA-N (4-phenylphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1C1=CC=CC=C1 XPEIJWZLPWNNOK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 125000001979 organolithium group Chemical group 0.000 claims abstract description 13
- -1 heterocyclic biphenylboronic acid compound Chemical class 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 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 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 9
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 230000008014 freezing Effects 0.000 abstract description 3
- 238000007710 freezing Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 235000010338 boric acid Nutrition 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- ZROXQGZENVFZJM-UHFFFAOYSA-N Brc1cccc(CN2C(CCC=C3)=C3C=NC2)c1 Chemical compound Brc1cccc(CN2C(CCC=C3)=C3C=NC2)c1 ZROXQGZENVFZJM-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- PYSLFXYFNIUQLE-UHFFFAOYSA-N dimethylaminooxyboronic acid Chemical compound CN(C)OB(O)O PYSLFXYFNIUQLE-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 present invention provides a kind of preparation methods of heterocycle biphenylboronic acid, and the preparation method comprises the following steps：Compound shown in Formulas I is dissolved in solvent A, borating agent and organolithium reagent are dissolved in solvent B, solvent A and solvent B are then subjected to continuous flowing charging reaction, is hydrolyzed using alkaline reagent the heterocycle biphenylboronic acid is obtained by the reaction after reaction；Preparation method provided by the present invention, by using flowing chemical technology synthesizing heterocyclic biphenylboronic acid compound, compared to existing popular response method, improve reaction yield, part of compounds yield can reach 82% or more, shorten the reaction time, it fast reaction can generally be completed within 1 hour, and improve reaction temperature, it can be completed at 20 DEG C to 10 DEG C above freezing or so, energy loss caused by being reacted in the environment of ultralow temperature is avoided, is a kind of excellent synthetic method, has a good application prospect.
Description
Technical field
The invention belongs to organic synthesis fields, are related to a kind of preparation method more particularly to a kind of heterocycle connection of heterocyclic boronic acids
The preparation method of phenyl boric acid.
Background technology
Continuous flowing chemistry is the new technology developed over the past decade.Because continuous flowing chemistry has, safety is high, passes
Hot mass transfer speed is fast, high degree of automation and the advantages that can monitor on-line and purify, and promotes it in organic synthesis
It is fast-developing.Thermal discharge it is larger, need the advantage in high temperature and pressure and the big reaction of environmental pollution particularly evident.Continuous liquidation
Technology is to provide power, the technology that reactant is chemically reacted with the continuous type of flow in microchannel with pump.Continuously
As a kind of emerging synthetic reaction technology, it has the potential advantage of response parameter height control technology, can carry flowing chemistry
High yield quality improves safety, and carry out high-temperature high-voltage reaction, high degree of automation is facilitated to reduce processing by hand, be easy to weight
It is multiple, it can purify online and scalable reaction, increase two-phase or the contact surface of three-phase system.In recent years in drug and intermediate
It is used widely in synthesis.
Heterocyclic boronic acid compounds are a kind of important organic synthesis intermediate, medicine intermediate and pesticide intermediate, are spread out
The downstream product born is numerous, especially has important application value in field of medicaments.The synthesis of various substitution aromatic ring boric acid is ground
Study carefully, foreign countries arise from or so the 1950s earliest, hereafter increasing to their application study, but currently, heterocycle boron
The synthesis technology of acid is concentrated mainly on conventional synthetic method, has very much limitation.
CN103601748A discloses a kind of hydroxyalkylation heterocyclic boronic acids ester and preparation method thereof, purposes, and step 1 is having
Under conditions of solvent and catalyst, heterocyclic compound and alkyl epoxide reaction generate compound A；Step 2, organic
Under conditions of solvent and catalyst, compound B is reacted with compound A or containing heterocyclic alcohol, you can, the method used for
Conventional synthetic method, can not carry out automatically controlling, and the artificial difficulty that manipulates is big, has limitation.
Therefore, how to develop a kind of novel method for synthesizing, can overcome presently, there are composition problem, this is for heterocycle
The synthesis of boric acid has great importance.
Invention content
It is an object of the invention to a kind of preparation methods of heterocycle biphenylboronic acid.
For this purpose, the present invention uses following technical scheme：
The present invention provides a kind of preparation methods of heterocycle biphenylboronic acid, and the preparation method comprises the following steps：By Formulas I
Shown compound is dissolved in solvent A, and borating agent and organolithium reagent are dissolved in solvent B, then by solvent A and solvent B into
The continuous flowing charging reaction of row, is hydrolyzed using alkaline reagent the heterocycle biphenylboronic acid is obtained by the reaction after reaction；
Compound has the following structure shown in the Formulas I：
Wherein Q is selected from bromine or iodine；
Any one of X and Y in nitrogen-atoms, oxygen atom, sulphur atom or methylene；
The value of n is 1 or 2.
Preparation method provided by the invention, by using flowing chemical technology, synthesizing heterocyclic biphenylboronic acid compound is compared
In existing popular response method, reaction yield is improved, part of compounds yield can reach 82% or more, shorten anti-
Between seasonable, it fast reaction can generally be completed within 1 hour, and improve reaction temperature, 10 DEG C of left sides above freezing can be arrived at -20 DEG C
Right completion avoids energy loss caused by being reacted in the environment of ultralow temperature, is a kind of excellent synthetic method.
Preferably, the borating agent is PinB(DMA).
In the present invention, borating agent selects PinB(DMA), can adapt to various complex environments
Reaction condition, compared to common boron such as triisopropyl borate ester, trimethylborate, butyl borate and bis- (pinacol combined) two boron
Base reagent has the characteristics that water sensitivity is low, stable structure, and reaction effect is more preferable.
Preferably, the organolithium reagent includes in n-BuLi, s-butyl lithium, tert-butyl lithium or lithium diisopropylamine
Any one.
Preferably, the solvent A and solvent B are independently selected from tetrahydrofuran or ether.
Preferably, the molar ratio of compound, borating agent and organolithium reagent shown in the Formulas I is 1:(1.1-2.5):
(1.1-2), such as can be 1:1.1:1.1、1:1.5:1.5、1:1.7:1.8、1:2:1.9 or 1:2.5:2.
Preferably, compound shown in the Formulas I relative to 1g, the dosage of solvent A are 5-10mL, for example, can be 5mL, 6mL,
7mL, 8mL, 9mL or 10mL.
Preferably, relative to the borating agent and organolithium reagent that gross mass is 1g, the dosage of solvent B is 1-3mL, such as
Can be 1mL, 1.5mL, 2mL, 2.5mL or 3mL.
Preferably, the continuous flowing charging reaction carries out in continuous charging reactor.
Preferably, the temperature of the continuous flowing charging reaction is -20 DEG C to 10 DEG C, for example, can be -20 DEG C, -15
DEG C, -10 DEG C, -5 DEG C, 0 DEG C, 5 DEG C or 10 DEG C.
In the present invention, by continuously flowing charging reaction, environment of the current conventional method needs in ultralow temperature is solved
Lower progress overcomes low temperature difficulty, improves operability, reduce energy consumption of reaction.
Preferably, it is described it is continuous flowing charging reaction time be 10-60min, such as can be 10min, 15min,
20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min or 60min.
Preferably, further include that reaction is quenched using saturated sodium-chloride after the continuous flowing charging reaction, it is mixed to carry out washing
Close solution.
Preferably, the alkaline reagent be sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate in any one or extremely
Few two kinds of combination.
Preferably, the time of the hydrolysis is 1-3h, such as can be 1h, 1.5h, 2h, 2.5h or 3h.
Preferably, the temperature of the hydrolysis is 20-40 DEG C, such as can be 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C or 40
℃。
Preferably, the preparation method specifically includes following steps：Compound shown in Formulas I is dissolved in solvent A, by boronation
Reagent and organolithium reagent are dissolved in solvent B, and wherein compound, borating agent and the molar ratio of organolithium reagent shown in Formulas I are
1:(1.1-2.5):(1.1-2) carries out continuous flowing charging reaction 10- then by solvent A and solvent B at -20 DEG C to 10 DEG C
Reaction is quenched through saturated sodium-chloride in 60min, after washing, reaction 1-3h is hydrolyzed at 20-40 DEG C using alkaline reagent and obtains
The heterocycle biphenylboronic acid.
Compared with the existing technology, the invention has the advantages that：
Preparation method provided by the invention, by using flowing chemical technology, synthesizing heterocyclic biphenylboronic acid compound is compared
In existing popular response method, reaction yield is improved, part of compounds yield can reach 82% or more, shorten anti-
Between seasonable, it fast reaction can generally be completed within 1 hour, and improve reaction temperature, 10 DEG C of left sides above freezing can be arrived at -20 DEG C
Right completion avoids energy loss caused by being reacted in the environment of ultralow temperature, is a kind of excellent synthetic method.
Preparation method operability provided by the invention is strong, is conducive to industrialized production and extensive preparation, has higher
Application prospect and good market application value.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright
, the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
The present embodiment prepares heterocycle biphenylboronic acid by following steps, and the structure that compounds of formula I has isSpecific reaction equation is as follows：
Compound shown in 0.01mol Formulas I is dissolved in solvent A tetrahydrofuran, by 0.012mol dimethylamino boric acid frequency which
Alcohol ester and 0.012mol n-BuLis are dissolved in solvent B tetrahydrofurans, are then connected solvent A and solvent B at -10 DEG C
Charging reaction 25min is moved in afterflow, and reaction is quenched through saturated sodium-chloride, after washing, is hydrolyzed at 30 DEG C using sodium hydroxide
Reaction 2h obtains 1- (3- phenyl boric acids)-pyrroles, yield 90.2%.
1H NMR(400MHz,DMSO-d6)δ7.49-7.08(m,4H),6.62-6.05(m,2H),4.79(s,2H)。
Embodiment 2
The present embodiment prepares heterocycle biphenylboronic acid by following steps, and the structure that compounds of formula I has isSpecific reaction equation is as follows：
Compound shown in Formulas I is dissolved in solvent A ether, PinB(DMA) and n-BuLi are dissolved in molten
In agent B ether, wherein compound, PinB(DMA) and the molar ratio of n-BuLi shown in Formulas I are 1:1.1:
1.1, then by solvent A and solvent B at 10 DEG C, continuous flowing charging reaction 10min is carried out, is quenched instead through saturated sodium-chloride
It answers, after washing, reaction 3h is hydrolyzed at 20 DEG C using potassium hydroxide and obtains 3- (3- benzyl boric acids)-oxazolidines, yield
88.3%.
1H NMR(400MHz,DMSO-d6)δ7.56-7.11(m,4H),4.83(s,2H),4.44(s,2H),3.47(t,
2H),2.53(t,2H)。
Embodiment 3
The present embodiment prepares heterocycle biphenylboronic acid by following steps, and the structure that compounds of formula I has isSpecific reaction equation is as follows：
Compound shown in Formulas I is dissolved in solvent A tetrahydrofuran, PinB(DMA) and s-butyl lithium is molten
In solvent B, wherein the molar ratio of compound, PinB(DMA) and s-butyl lithium shown in Formulas I is 1:2.5:2,
Then by solvent A and solvent B at -20 DEG C, continuous flowing charging reaction 60min is carried out, reaction is quenched through saturated sodium-chloride, washes
After washing, reaction 1h is hydrolyzed at 40 DEG C using alkaline reagent and obtains 1- (3- benzyl boric acids) -1H- indazoles, yield 87.2%.
1H NMR(400MHz,DMSO-d6)δ8.20-8.14(m,1H),7.91-7.03(m,8H),4.99(s,2H),4.22
(s,2H)。
Embodiment 4
Difference lies in the borating agent in the present embodiment is triisopropyl borate ester to the present embodiment, remaining is with embodiment 1
It is same as Example 1,1- (3- phenyl boric acids)-pyrroles, yield 80.1% is prepared.
Embodiment 5
The present embodiment and embodiment 1 difference lies in, the borating agent in the present embodiment is trimethylborate, remaining with
Embodiment 1 is identical, and 1- (3- phenyl boric acids)-pyrroles, yield 82.3% is prepared.
Embodiment 6
The present embodiment and embodiment 1 difference lies in, the reaction temperature in the present embodiment is -55 DEG C, remaining with implementation
Example 1 is identical, and 1- (3- phenyl boric acids)-pyrroles, yield 87.6% is prepared.
Comparative example 1
Difference lies in, this comparative examples for this comparative example and embodiment 1 according to popular response method, by compound shown in Formulas I,
PinB(DMA) and n-BuLi are dissolved in tetrahydrofuran, in eggplant-shape bottle, under nitrogen protection, at -78 DEG C into
1- (3- phenyl boric acids)-pyrroles, yield 79.5% is obtained by the reaction in row.
By the comparison of embodiment 1 and embodiment 4-5 it is found that when the borating agent in the present invention replaces with other reagents
When, the yield of reaction is declined, and illustrates that the PinB(DMA) in the present invention is more suitable for carrying out in this environment
Reaction, improves yield.
By the comparison of embodiment 1 and embodiment 6 it is found that when reaction temperature reduces in the present invention, yield decreases,
It illustrates that the present invention can react at relatively high temperatures, promotes reaction yield.
By the comparison of embodiment 1 and comparative example 1 it is found that when being prepared using conventional reaction method, reaction yield is big
Amplitude reduction illustrates that the present invention by flowing chemical technology, substantially increases the yield of reaction.
To sum up, preparation method high income provided by the invention, operability is strong, has a good application prospect and apply valence
Value.
Applicant states that the present invention illustrates the preparation method of the heterocycle biphenylboronic acid of the present invention by above-described embodiment,
But the invention is not limited in above-mentioned method detaileds, that is, do not mean that the present invention has to rely on above-mentioned method detailed and could implement.
Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, equivalent the replacing to each raw material of product of the present invention
It changes and the addition of auxiliary element, the selection of concrete mode etc., all falls within protection scope of the present invention and the open scope.
Claims (10)
1. a kind of preparation method of heterocycle biphenylboronic acid, which is characterized in that the preparation method comprises the following steps：By Formulas I institute
Show that compound is dissolved in solvent A, borating agent and organolithium reagent are dissolved in solvent B, then carries out solvent A and solvent B
Continuous flowing charging reaction, is hydrolyzed using alkaline reagent the heterocycle biphenylboronic acid is obtained by the reaction after reaction；
Compound has the following structure shown in the Formulas I：
Wherein Q is selected from bromine or iodine；
Any one of X and Y in nitrogen-atoms, oxygen atom, sulphur atom or methylene；
The value of n is 1 or 2.
2. preparation method according to claim 1, which is characterized in that the borating agent is dimethylamino boric acid pinacol
Ester.
3. preparation method according to claim 1 or 2, which is characterized in that the organolithium reagent includes n-BuLi, secondary
Any one in butyl lithium, tert-butyl lithium or lithium diisopropylamine.
4. preparation method according to any one of claim 1-3, which is characterized in that the solvent A and solvent B are independent
Ground is selected from tetrahydrofuran or ether.
5. according to the preparation method described in any one of claim 1-4, which is characterized in that compound, boronation shown in the Formulas I
The molar ratio of reagent and organolithium reagent is 1:(1.1-2.5):(1.1-2).
6. preparation method according to any one of claims 1-5, which is characterized in that chemical combination shown in the Formulas I relative to 1g
The dosage of object, solvent A is 5-10mL；
Preferably, relative to the borating agent and organolithium reagent that gross mass is 1g, the dosage of solvent B is 1-3mL.
7. according to the preparation method described in any one of claim 1-6, which is characterized in that the continuous flowing charging reaction exists
It is carried out in continuous charging reactor；
Preferably, the temperature of the continuous flowing charging reaction is -20 DEG C to 10 DEG C；
Preferably, the time of the continuous flowing charging reaction is 10-60min.
8. according to the preparation method described in any one of claim 1-7, which is characterized in that after the continuous flowing charging reaction
Further include that reaction is quenched using saturated sodium-chloride, carries out washing mixed solution.
9. according to the preparation method described in any one of claim 1-8, which is characterized in that the alkaline reagent is hydroxide
In sodium, potassium hydroxide, potassium carbonate or sodium carbonate any one or at least two combination；
Preferably, the time of the hydrolysis is 1-3h；
Preferably, the temperature of the hydrolysis is 20-40 DEG C.
10. according to the preparation method described in any one of claim 1-9, which is characterized in that the preparation method specifically includes
Following steps：Compound shown in Formulas I is dissolved in solvent A, borating agent and organolithium reagent are dissolved in solvent B, wherein Formulas I
The molar ratio of shown compound, borating agent and organolithium reagent is 1:(1.1-2.5):(1.1-2), then by solvent A and molten
Agent B carries out continuous flowing charging reaction 10-60min, reaction is quenched through saturated sodium-chloride at -20 DEG C to 10 DEG C, after washing,
Reaction 1-3h is hydrolyzed at 20-40 DEG C using alkaline reagent and obtains the heterocycle biphenylboronic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810330233.6A CN108409767B (en) | 2018-04-13 | 2018-04-13 | Preparation method of heterocyclic biphenyl boric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810330233.6A CN108409767B (en) | 2018-04-13 | 2018-04-13 | Preparation method of heterocyclic biphenyl boric acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108409767A true CN108409767A (en) | 2018-08-17 |
| CN108409767B CN108409767B (en) | 2020-07-10 |
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| US12029744B2 (en) | 2019-04-12 | 2024-07-09 | Riboscience Llc | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1665824A (en) * | 2002-07-03 | 2005-09-07 | 辉瑞产品公司 | Substituted aryl boronic acids, their preparation and their precursors |
| EP2862864A1 (en) * | 2013-10-18 | 2015-04-22 | Yriel | Continuous method for preparing boronic acids and derivatives thereof |
| CN106188116A (en) * | 2016-07-14 | 2016-12-07 | 沧州普瑞东方科技有限公司 | A kind of method of synthesizing pyrazole 4 boric acid pinacol ester |
| CN106478707A (en) * | 2016-10-14 | 2017-03-08 | 大连九信精细化工有限公司 | A kind of method that utilization continuous flow reactor produces 3 difluoro-methoxy 5 fluorobenzoic boric acid |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1665824A (en) * | 2002-07-03 | 2005-09-07 | 辉瑞产品公司 | Substituted aryl boronic acids, their preparation and their precursors |
| EP2862864A1 (en) * | 2013-10-18 | 2015-04-22 | Yriel | Continuous method for preparing boronic acids and derivatives thereof |
| CN106188116A (en) * | 2016-07-14 | 2016-12-07 | 沧州普瑞东方科技有限公司 | A kind of method of synthesizing pyrazole 4 boric acid pinacol ester |
| CN106478707A (en) * | 2016-10-14 | 2017-03-08 | 大连九信精细化工有限公司 | A kind of method that utilization continuous flow reactor produces 3 difluoro-methoxy 5 fluorobenzoic boric acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12029744B2 (en) | 2019-04-12 | 2024-07-09 | Riboscience Llc | Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
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