CN105669731B - A kind of synthetic method of 4 (4 alkyl epoxide) phenyl boric acids - Google Patents
A kind of synthetic method of 4 (4 alkyl epoxide) phenyl boric acids Download PDFInfo
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- CN105669731B CN105669731B CN201610011056.6A CN201610011056A CN105669731B CN 105669731 B CN105669731 B CN 105669731B CN 201610011056 A CN201610011056 A CN 201610011056A CN 105669731 B CN105669731 B CN 105669731B
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- phenyl boric
- boric acid
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- 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 System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present invention provides a kind of synthetic method of 4 (4 alkyl epoxide) phenyl boric acids.4 (alkenyloxy group of alkyl 2) bromobenzenes are generated using 4 bromophenols and the alkyl alkene reaction of 3 bromine 6, the intermediate then reacts with magnesium metal generation RMgBr and trimethylborate, after being quenched, organic layer adds catalytic hydrogenation, obtains 4 (4 alkyl epoxide) phenyl boric acids.The process synthesis yield is high, it is to avoid it is a large amount of it is useless it is solid produce, improve the market core competitiveness of product.
Description
Technical field
The present invention relates to a kind of synthetic method of 4- (4- alkyls epoxide) phenyl boric acid, belong to fine-chemical intermediate neck
Domain.
Background technology
1- phosphoric acid sheath amine alcohols（S1P）It is originally found relevant with the regulation of cell growth, it is that one kind is present in nucleus
Lipid courier with bioactivity, by sphingosine kinase hypotype 1（SphK1）Produce.S1P by TRAF2 regulate and control TNF-a and
NF- к B signal paths, and then participate in a series of inflammation, anti-apoptotic and immune response.S1P regulation reagents have for pharmaceutical synthesis
Great importance, current existing structure（Formulas I）It is as follows：
It is related to the synthesis of key intermediate hexamethylene oxygen phenyl boric acid, document in the class formation（With reference to：WO2014081756）
Preparation method be mainly：4- substituted cyclohexanols or cyclohexyl bromide obtain hexamethylene after being reacted using Mitsunobu with 4- bromophenols
Methoxyl bromobenzene, the method being then coupled using Suzuki again obtains corresponding borate.Mitsunobu reactions can be produced in the method
The useless solid or raw material cyclohexyl bromide such as the substantial amounts of triphenylphosphine oxide of life occurs competitive elimination causes 4- bromophenols a large amount of with substitution
Residue, the method cost of coupling is also of a relatively high, and these all limit the extensive use of the synthetic method.
The content of the invention
In order to overcome drawbacks described above, the present invention to provide a kind of synthetic method of 4- (4- alkyls epoxide) phenyl boric acid.Adopt
Generate 4- (alkyl -2- alkenyloxy groups) bromobenzene with 4- bromophenols and the bromo- 6- alkyls alkene reactions of 3-, the intermediate then with
Magnesium metal generates RMgBr and is reacted with trimethylborate, and after being quenched, organic layer adds catalytic hydrogenation, obtains 4- (4- alkyl rings
Hexyloxy) phenyl boric acid.
A kind of synthetic method of 4- (4- alkyls epoxide) phenyl boric acid, it is characterised in that including following operating procedure：
The first step：In the presence of an inorganic base, by p bromophenol and the bromo- 6- alkyl cyclohexenes addition solvents of 3-, room temperature is stirred
Reaction is mixed, after reaction terminates, saturated ammonium chloride solution layering is added, after organic layer is evaporated, band once, obtains 4- again to add toluene
(4- alkyl -2- alkenyloxy groups) bromobenzene crude product, is used directly in the next step, this step yield 85-93%；
Second step：Above-mentioned intermediate is added in magnesium metal and anhydrous tetrahydro furan, and RMgBr is prepared into after initiation, is controlled
Under the conditions of -70 DEG C to -10 DEG C of temperature, reaction in borate is added dropwise to, reaction terminates, adds hydrochloric acid reaction, be layered, water layer is again
Secondary adopting is extracted with ethyl acetate, and merges organic layer, after adding palladium-carbon catalyst, is passed through 1 atmospheric pressure hydrogen and is reduced, reaction knot
Beam, filters out catalyst, and solvent evaporated obtains product, this step yield 60-82% after ethanol and the mashing of normal heptane mixed solvent.
Further, in the above-mentioned technical solutions, in the first step, inorganic base is selected from:Potassium carbonate, sodium carbonate, carbonic acid
Hydrogen sodium, saleratus or cesium carbonate.
Further, in the above-mentioned technical solutions, in the first step, solvent is selected from:Tetrahydrofuran, dioxane,
DMSO or DMF.
Further, in the above-mentioned technical solutions, in the first step, in the bromo- 6- alkyl cyclohexenes of 3-, alkyl is selected from
Hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl or the tert-butyl group.
Further, in the above-mentioned technical solutions, in the first step, the bromo- 6- alkyl cyclohexenes of p bromophenol, 3- and nothing
Machine alkali equivalent ratio is 1:1-1.3:1-5.
Further, in the above-mentioned technical solutions, in the second step, borate is selected from trimethylborate or boric acid three is different
Propyl ester.
Further, in the above-mentioned technical solutions, in the second step, 4- (4- alkyl -2- alkenyloxy groups) bromobenzene, gold
Category magnesium is 1 with borate equivalent proportion:1-1.2:1-1.5.
Further, in the above-mentioned technical solutions, in the second step, palladium-carbon catalyst is selected from 5% or 10% two kind of specification,
The amount for being added is the 3-10% of 4- (4- alkyl -2- alkenyloxy groups) bromobenzene crude product weight.
Invention beneficial effect：
The technique is high using alkenyl bromine reaction activity by the way of roundabout compared with literature method, is then deposited in boric acid
It is lower can be reduced by smoothly realizing double bond in the way of, improve reaction yield, it is to avoid a large amount of useless solid in Mitsunobu reactions
Triphenylphosphine oxide, and a large amount of elimination by-product cyclic hexenes during using cyclohexyl bromide.Boric acid is prepared using grignard method and replaces even
Connection, reduces reaction cost, further increases the core competitive of process route.
Specific embodiment:
Embodiment 1:
The synthesis of 4- cyclohexyloxy phenyl boric acids：
The first step：P bromophenol (17.3 grams, 0.10mol) and 3- bromines cyclohexene (17.7 grams, 0.11mol) are added 130
In milliliter DMSO, potassium carbonate (20.7 grams, 0.15mol) is then added, reaction is stirred at room temperature, after reaction terminates, add saturation
Ammonium chloride solution adjusts PH=5-6, and layering, semi-saturation salt is washed, and after organic layer is evaporated, band once, obtains 23.0 again to add toluene
Gram 4- (hexamethylene -2- alkenyloxy groups) bromobenzene solid crude product, GC:95.5%；
Second step：Above-mentioned intermediate adds magnesium metal (2.4 grams, 0.10mol) and 15 milliliters of tetrahydrofurans, plus iodine to trigger
Afterwards, 23.0 grams of 4- (hexamethylene -2- alkenyloxy groups) bromobenzene is dissolved in into 110 milliliters of tetrahydrofuran solution remainders all to add, is returned
RMgBr is obtained after stream reaction.After being down to room temperature, -20 DEG C to -10 DEG C of temperature control, be added dropwise to trimethylborate (13.5 grams,
0.13mol) it is dissolved in 40 milliliters of tetrahydrofurans.Reaction terminates, and adds 10% hydrochloric acid to adjust PH=2-3, layering, water layer to use again
110 milliliters of ethyl acetate extractions, merge organic layer, add 2.2 gram of 5% palladium-carbon catalyst, are passed through 1 atmospheric pressure hydrogen and are reduced.
After reaction terminates, catalyst, solvent evaporated, ethanol and normal heptane (30 are filtered out:1) off-white color is obtained after mixed solvent mashing to consolidate
14.1 grams of body product, HPLC：99.1%, two step yields 64%.
Embodiment 2:
The synthesis of 4- (4- methyl cyclohexanes epoxide) phenyl boric acid：
The first step：By p bromophenol (17.3 grams, 0.10mol) and the bromo- 6- methylcyclohexenes of 3- (17.5 grams, 0.10mol)
Add in 100 milliliters of DMSO, then add cesium carbonate (32.6 grams, 0.10mol), reaction is stirred at room temperature, after reaction terminates, plus
Enter saturated ammonium chloride solution and adjust PH=5-6, layering, semi-saturation salt is washed, after organic layer is evaporated, band once, is obtained again to add toluene
To 23.5 grams of 4- (4- methyl cyclohexane -2- alkenyloxy groups) bromobenzene solid crude products, GC:96.3%；
Second step：Above-mentioned intermediate adds magnesium metal (2.2 grams, 0.09mol) and 15 milliliters of tetrahydrofurans, plus iodine to trigger
Afterwards, 23.5 grams of 4- (hexamethylene -2- alkenyloxy groups) bromobenzene is dissolved in into 110 milliliters of tetrahydrofuran solution remainders all to add, is returned
RMgBr is obtained after stream reaction.After being down to room temperature, -30 DEG C to -20 DEG C of temperature control, be added dropwise to trimethylborate (10.4 grams,
0.10mol) it is dissolved in 40 milliliters of tetrahydrofurans.Reaction terminates, and adds 10% hydrochloric acid to adjust PH=2-3, layering, water layer to use again
110 milliliters of ethyl acetate extractions, merge organic layer, add 1.1 gram of 10% palladium-carbon catalyst, are passed through 1 atmospheric pressure hydrogen and are gone back
It is former.After reaction terminates, catalyst, solvent evaporated, ethanol and normal heptane (30 are filtered out:1) to obtain class white after mixed solvent mashing
13.8 grams of color solid product, HPLC：98.6%, two step yields 59%.
Embodiment 3:
The synthesis of 4- (4- cyclohexyls epoxide) phenyl boric acid：
The first step：By p bromophenol (17.3 grams, 0.10mol) and the bromo- 6- ethyl-cyclohexenes of 3- (20.8 grams, 0.11mol)
Add in 110 milliliters of DMF, then add sodium carbonate (21.2 grams, 0.20mol), reaction is stirred at room temperature, after reaction terminates, plus
Enter saturated ammonium chloride solution and adjust PH=5-6, layering, semi-saturation salt is washed, after organic layer is evaporated, band once, is obtained again to add toluene
To 25.3 grams of 4- (4- cyclohexyl -2- alkenyloxy groups) bromobenzene solid crude products, GC:97.8%；
Second step：Above-mentioned intermediate adds magnesium metal (2.5 grams, 0.10mol) and 12 milliliters of tetrahydrofurans, plus iodine to trigger
Afterwards, 25.3 grams of 4- (hexamethylene -2- alkenyloxy groups) bromobenzene is dissolved in into 120 milliliters of tetrahydrofuran solution remainders all to add, is returned
RMgBr is obtained after stream reaction.After being down to room temperature, -70 DEG C to -60 DEG C of temperature control, be added dropwise to trimethylborate (12.5 grams,
0.12mol) it is dissolved in 40 milliliters of tetrahydrofurans.Reaction terminates, and adds 10% hydrochloric acid to adjust PH=2-3, layering, water layer to use again
130 milliliters of ethyl acetate extractions, merge organic layer, add 2.5 gram of 5% palladium-carbon catalyst, are passed through 1 atmospheric pressure hydrogen and are reduced.
After reaction terminates, catalyst, solvent evaporated, ethanol and normal heptane (20 are filtered out:1) white solid is obtained after mixed solvent mashing
17.1 grams of product, HPLC：98.2%, two step yields 69%.
Claims (8)
1. the synthetic method of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid, it is characterised in that including
Following operating procedure：
The first step：In the presence of an inorganic base, p bromophenol and 3- bromines cyclohexene or the bromo- 6- alkyl cyclohexenes of 3- are added into solvent
In, reaction is stirred at room temperature, after reaction terminates, saturated ammonium chloride solution layering is added, after organic layer is evaporated, add toluene band one again
It is secondary, 4- (hexamethylene -2- alkenyloxy groups) bromobenzenes or 4- (4- alkyl -2- alkenyloxy groups) bromobenzene crude product are obtained, it is directly used in lower step anti-
Ying Zhong, this step yield 85-93%；
Second step：Above-mentioned intermediate is added in magnesium metal and anhydrous tetrahydro furan, and RMgBr, temperature control -70 are prepared into after initiation
DEG C react under the conditions of -10 DEG C, being added dropwise in borate, reaction terminates, and adds hydrochloric acid reaction, and layering, water layer is adopted again
It is extracted with ethyl acetate, merges organic layer, after adding palladium-carbon catalyst, be passed through 1 atmospheric pressure hydrogen and reduced, reaction terminates,
Catalyst is filtered out, solvent evaporated obtains product, this step yield 60-82% after ethanol and the mashing of normal heptane mixed solvent.
2. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In the first step, inorganic base is selected from：Potassium carbonate, sodium carbonate, sodium acid carbonate, saleratus or cesium carbonate.
3. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In the first step, solvent is selected from：Tetrahydrofuran, dioxane, DMSO or DMF.
4. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In the first step, in the bromo- 6- alkyl cyclohexenes of 3-, alkyl is selected from methyl, ethyl, n-propyl, isopropyl, just
Butyl or the tert-butyl group.
5. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In the first step, p bromophenol, 3- bromines cyclohexene or the bromo- 6- alkyl cyclohexenes of 3- and inorganic base equivalents ratio are
1:1-1.3:1-5。
6. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In second step, borate is selected from trimethylborate or triisopropyl borate ester.
7. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In second step, 4- (hexamethylene -2- alkenyloxy groups) bromobenzenes or 4- (4- alkyl -2- alkenyloxy groups) bromobenzene, gold
Category magnesium is 1 with borate equivalent proportion:1-1.2:1-1.5.
8. the synthesis side of a kind of 4- cyclohexyloxies phenyl boric acid or 4- (4- alkyls epoxide) phenyl boric acid according to claim 1
Method, it is characterised in that：In second step, palladium-carbon catalyst is selected from 5% or 10% two kind of specification, and the amount for being added is 4- (hexamethylene -2- alkene
Epoxide) bromobenzene or 4- (4- alkyl -2- alkenyloxy groups) bromobenzene crude product weight 3-10%.
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