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
- epoxide
- alkyl
- alkyls
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- -1 alkyl epoxide Chemical class 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- 239000012044 organic layer Substances 0.000 claims abstract description 12
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 9
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 150000004768 bromobenzenes Chemical class 0.000 claims abstract 3
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 28
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 238000005360 mashing Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical class OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 abstract 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- 125000003302 alkenyloxy group Chemical group 0.000 abstract 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 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
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical class BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 1
- LJARGIJYLCKLNH-UHFFFAOYSA-N 1-bromo-6-ethylcyclohexene Chemical class BrC1=CCCCC1CC LJARGIJYLCKLNH-UHFFFAOYSA-N 0.000 description 1
- JNJOTSRJOBHFBW-UHFFFAOYSA-N 1-bromo-6-methylcyclohexene Chemical class CC1CCCC=C1Br JNJOTSRJOBHFBW-UHFFFAOYSA-N 0.000 description 1
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 description 1
- FDEHVZFOSJPORA-UHFFFAOYSA-N C1(CCCCC1)OC1=CC=C(C=C1)OB(O)O Chemical class C1(CCCCC1)OC1=CC=C(C=C1)OB(O)O FDEHVZFOSJPORA-UHFFFAOYSA-N 0.000 description 1
- 101100150085 Caenorhabditis elegans sphk-1 gene Proteins 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
- 206010061218 Inflammation Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 102000004393 TNF receptor-associated factor 2 Human genes 0.000 description 1
- 108090000925 TNF receptor-associated factor 2 Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000006368 anti-apoptosis response Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical class OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 108010035597 sphingosine kinase Proteins 0.000 description 1
- 238000006467 substitution reaction Methods 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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