CN108659024A - The preparation method of gram vertical boron sieve - Google Patents
The preparation method of gram vertical boron sieve Download PDFInfo
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- CN108659024A CN108659024A CN201810820495.0A CN201810820495A CN108659024A CN 108659024 A CN108659024 A CN 108659024A CN 201810820495 A CN201810820495 A CN 201810820495A CN 108659024 A CN108659024 A CN 108659024A
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- 229910052796 boron Inorganic materials 0.000 title claims abstract description 37
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000003960 organic solvent Substances 0.000 claims abstract description 22
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims abstract description 14
- 239000011550 stock solution Substances 0.000 claims abstract description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 8
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 8
- -1 triisopropyl borate ester Chemical class 0.000 claims abstract description 5
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims abstract description 5
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims abstract description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940061627 chloromethyl methyl ether Drugs 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 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
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 2
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- 241000790917 Dioxys <bee> Species 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 230000008901 benefit Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 208000033641 Ring chromosome 5 syndrome Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- MXOSTENCGSDMRE-UHFFFAOYSA-N butyl-chloro-dimethylsilane Chemical compound CCCC[Si](C)(C)Cl MXOSTENCGSDMRE-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940094989 trimethylsilane Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- XYECOASIWBAIJK-UHFFFAOYSA-N N#Cc(cc1)ccc1Oc(cc1)cc2c1S(O)OC2 Chemical compound N#Cc(cc1)ccc1Oc(cc1)cc2c1S(O)OC2 XYECOASIWBAIJK-UHFFFAOYSA-N 0.000 description 1
- IEHZPKWXBVTRRG-UHFFFAOYSA-N N#Cc(cc1)ccc1Oc(cc1C=O)ccc1Br Chemical compound N#Cc(cc1)ccc1Oc(cc1C=O)ccc1Br IEHZPKWXBVTRRG-UHFFFAOYSA-N 0.000 description 1
- DAMOSKSUIVLOJT-UHFFFAOYSA-N N#Cc(cc1)ccc1Oc(cc1CO)ccc1Br Chemical compound N#Cc(cc1)ccc1Oc(cc1CO)ccc1Br DAMOSKSUIVLOJT-UHFFFAOYSA-N 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- LBZRRXXISSKCHV-UHFFFAOYSA-N [B].[O] Chemical compound [B].[O] LBZRRXXISSKCHV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000005189 cardiac health Effects 0.000 description 1
- 239000003795 chemical substances by application 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- DKTXXUNXVCHYDO-UHFFFAOYSA-N phenoxyborinic acid Chemical compound OBOC1=CC=CC=C1 DKTXXUNXVCHYDO-UHFFFAOYSA-N 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 238000005406 washing 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)
Abstract
The invention discloses the preparation methods of a kind of gram of vertical boron sieve, including type I compound and alkali metal borohydride haptoreaction, obtain Formula II compound；Formula II compound and compound a haptoreaction obtain III compound of formula；Or Formula II compound and dihydropyran haptoreaction, obtain III compound of formula；Compound a is trim,ethylchlorosilane, tert-butyl chloro-silicane or chloromethyl methyl ether；Compound shown in formula III and isopropylmagnesium chloride solution haptoreaction, obtain stock solution；Stock solution is added compound b and carries out haptoreaction with the mixed liquor of third organic solvent, adds hydrochloric acid haptoreaction, obtains gram vertical boron sieve, the compound as shown in formula IV；Compound b is 2 alkoxy, 4,4,5,5 tetramethyl, 1,3,2 dioxy boron, penta ring, triisopropyl borate ester or trimethylborate；
Description
Technical field
The invention belongs to pharmaceutical technology fields, more particularly, to the preparation method of a kind of gram of vertical boron sieve.
Background technology
Eczema is the allergic inflammation dermatoses caused by a variety of internal and external factors, multiform damage symmetrical with skin lesion,
Acute pruritus has and oozes out tendency, recurrent exerbation etc. for notable feature, this disease is touching refractory, and clinical treatment is intractable, to the body of patient
Heart health causes larger impact.Currently, western medicine is with Loratadine, glucocorticoid and convergence, protection preparation etc.
Based on symptomatic treatment, though such drug can control symptom, easily recurred after being discontinued, and it is long-term, repeatedly, large area use can cause
The adverse reactions such as the telangiectasis of infant part, cutaneous pigmentation.Gram vertical boron sieve is non-hormone drug, has user
The advantages such as just, adverse reaction is small, recurrence rate is low have higher clinical value.
As depicted in figs. 1 and 2, existing synthesis 4- ((penta ring -5- of 1- hydroxyls -1,3- dihydrobenzo [C] [1,2] oxa- boron
Base) oxygen) benzonitrile (gram vertical boron sieve) method in, some with organic palladium carry out coupling generate borate, some butyl lithiums or
Tert-butyl lithium is reacted in -78 DEG C and trimethylborate or triisopropyl borate ester, generates phenyl boronate；In above-mentioned preparation side
In method, there are organic palladium catalyst is expensive, and product palladium is caused to remain, butyl lithium or tert-butyl lithium severe reaction conditions,
The problems such as process costs are high.
Invention content
The object of the present invention is to provide the new preparation process of a kind of gram of vertical boron sieve, which is not related to organic palladium chtalyst
The reaction condition of agent and harshness, process costs are low, can preferably be applied to industrialized production.
To achieve the goals above, the present invention provides the preparation method of a kind of gram of vertical boron sieve, which includes such as
Lower step：
(1) in the presence of the first solvent, compound shown in formula I and alkali metal borohydride is subjected to haptoreaction, obtained
To Formula II compound represented；
(2) in the presence of the second organic solvent and alkali, the Formula II compound represented and compound a are contacted
Reaction, obtains compound shown in formula III；Or in the presence of the second organic solvent and catalyst, by chemical combination shown in the Formula II
Object and dihydropyran carry out haptoreaction, obtain compound shown in formula III；Wherein, the compound a is trim,ethylchlorosilane, uncle
Butyldimethylchlorosilane or chloromethyl methyl ether；
Wherein, wherein R is trimethylsilyl, t-butyldimethylsilyi, dimethyl cellosolve base or THP trtrahydropyranyl；
(3) in the presence of third organic solvent and protective gas, by compound shown in the formula III and isopropyl chlorination
Magnesium solution carries out haptoreaction, obtains stock solution；Then compound b and third organic solvent is added in the stock solution
Haptoreaction is carried out in mixed liquor, adds hydrochloric acid haptoreaction, obtains gram vertical boron sieve, the compound as shown in formula IV；Wherein, institute
It is penta ring of 2- alkoxy -4,4,5,5- tetramethyl -1,3,2- dioxies boron, triisopropyl borate ester or trimethylborate to state compound b；
Technical scheme of the present invention has the following advantages that：
(1) borate for preparing of the invention substitutes organic palladium catalyst using grignard reagent in the process, cheap, reaction
Mild condition not will produce palladium residual.
(2) preparation method of the invention need not be reacted under harsh Cryogenic Conditions.
(3) preparation method process costs of the invention are low, and cost of material is cheap, can preferably be applied to industrial metaplasia
Production.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Description of the drawings
Exemplary embodiment of the invention is described in more detail in conjunction with the accompanying drawings, it is of the invention above-mentioned and its
Its purpose, feature and advantage will be apparent, wherein in exemplary embodiment of the invention, identical reference label
Typically represent same parts.
Fig. 1 shows the synthetic route chart of a kind of gram of vertical boron sieve in the prior art.
Fig. 2 shows the synthetic route charts of another gram vertical boron sieve in the prior art.
Fig. 3 shows the synthetic route chart of according to the present invention gram of vertical boron sieve.
Specific implementation mode
The preferred embodiment of the present invention is described in more detail below.Although the following describe the preferred implementations of the present invention
Mode, however, it is to be appreciated that may be realized in various forms the present invention without should be limited by embodiments set forth herein.Phase
Instead, these embodiments are provided so that the present invention is more thorough and complete, and can be by the scope of the present invention completely
It is communicated to those skilled in the art.
As shown in figure 3, the present invention provides the preparation method of a kind of gram of vertical boron sieve, which includes the following steps：
(1) in the presence of the first solvent, compound shown in formula I and alkali metal borohydride is subjected to haptoreaction, obtained
To Formula II compound represented；
(2) in the presence of the second organic solvent and alkali, the Formula II compound represented and compound a are contacted
Reaction, obtains compound shown in formula III；Or in the presence of the second organic solvent and catalyst, by chemical combination shown in the Formula II
Object and dihydropyran carry out haptoreaction, obtain compound shown in formula III；Wherein, the compound a is trim,ethylchlorosilane, uncle
Butyldimethylchlorosilane or chloromethyl methyl ether；
Wherein, wherein R is trimethylsilyl, t-butyldimethylsilyi, dimethyl cellosolve base or THP trtrahydropyranyl；
(3) in the presence of third organic solvent and protective gas, by compound shown in the formula III and isopropyl chlorination
Magnesium solution carries out haptoreaction, obtains stock solution；Then compound b and third organic solvent is added in the stock solution
Haptoreaction is carried out in mixed liquor, adds hydrochloric acid haptoreaction, obtains gram vertical boron sieve, the compound as shown in formula IV；Wherein, institute
It is penta ring of 2- alkoxy -4,4,5,5- tetramethyl -1,3,2- dioxies boron, triisopropyl borate ester or trimethylborate to state compound b；
In accordance with the present invention it is preferred that in step (1), the dosage of the alkali metal borohydride is chemical combination shown in the formula I
The 0.5-1 equivalents of object；The alkali metal borohydride is sodium borohydride and/or potassium borohydride；First solvent is methanol, second
At least one of alcohol, isopropanol, water and tetrahydrofuran.
In accordance with the present invention it is preferred that in step (2), second organic solvent is dichloromethane, tetrahydrofuran, toluene
At least one of with N,N-dimethylformamide；The alkali be organic base and/or inorganic base, the organic base be triethylamine,
At least one of tri-n-butylamine, diisopropylethylamine and imidazoles, the inorganic base are sodium hydride, sodium hydroxide, potassium hydroxide, carbon
At least one of sour sodium and potassium carbonate；The catalyst is p-methyl benzenesulfonic acid.
In accordance with the present invention it is preferred that in step (3), by compound shown in the formula III and isopropylmagnesium chloride solution into
The catalytic reaction condition of row includes：In the presence of protective gas, the isopropylmagnesium chloride solution is added dropwise to III institute of formula
It is -20-0 DEG C that temperature is kept during showing compound and in the mixed liquor of third organic solvent, being added dropwise.
In accordance with the present invention it is preferred that in step (3), the reaction condition of compound shown in formula IV includes：It will be described standby
The compound b is added dropwise to the mixed liquor of third organic solvent with solution, and the stock solution has been added in 1-2h, 0-
25 DEG C of reaction 6-12h, it is 3 hereinafter, the reaction was continued 3-7h that hydrochloric acid to pH value is then added under condition of ice bath；It is as one preferred
The reaction temperature of embodiment, the reaction was continued the 3-7h is 10-30 DEG C；Preferably, the mass concentration of the hydrochloric acid is 10-
37.5%.
In accordance with the present invention it is preferred that in step (3), the amount of the isopropylmagnesium chloride in the isopropylmagnesium chloride solution
For the 1-2.5 equivalents of compound shown in the formula III；The dosage of the compound b is the 1-2.5 equivalents of the stock solution；Institute
It is at least one of tetrahydrofuran, ether, methyltetrahydrofuran and glycol dimethyl ether to state third organic solvent.
In accordance with the present invention it is preferred that in step (3), the 2- alkoxies -4,4,5,5- tetramethyls -1,3,2- dioxy boron
Alkoxy in penta ring is preferably the alkoxy of C1-C4；2- alkoxies -4,4,5,5- tetramethyl -1,3,2- dioxies the boron penta
Ring is more preferably penta ring of 2- methoxyl group -4,4,5,5- tetramethyl -1,3,2- dioxies boron and/or 2- isopropyls alkoxy -4,4,
Penta ring of 5,5- tetramethyl -1,3,2- dioxies boron.
It further illustrates the present invention by the following examples：
Embodiment
The present embodiment provides the preparation method of a kind of gram of vertical boron sieve, which includes the following steps：
(1) preparation of 4- [(the bromo- 3- methylols of 4-) phenoxy group)] benzonitrile (compound shown in Formula II)
By 30.2g (0.1mol) 4- [(the bromo- 3- formoxyls of 4-) phenoxy group)] benzonitrile (compound shown in formula I), 400ml
Methanol is added in reaction kettle, and 1.89g (0.1mol) sodium borohydride is added portionwise, finishes, and continues to stir 4h at 25 DEG C to raw material
The reaction was complete, recycles methanol, and the mashing of 1000ml water is added, filters, dry, obtains solid 27.8, yield 92%；
(2) [5- (4- cyanophenoxies) -2- bromophenyl -1- methoxyl groups]-trimethyl silane (compound shown in formula III)
It prepares
By 30.2g (0.1mol) 4- [(the bromo- 3- methylols of 4-) phenoxy group)] benzonitrile, 300ml dichloromethane, 30.3g tri-
Ethamine (0.3mol) is added in reaction kettle, is cooled to 0-10 DEG C, and 12.96g trim,ethylchlorosilanes are added dropwise, and control temperature is no more than
10 DEG C, 25 DEG C of stirrings for 24 hours, add water quenching reaction, dichloromethane extraction, washing, anhydrous magnesium sulfate drying, filtering, recycling design
Obtain grease 31.8g, yield 85%；
(3) 4- ((penta ring -5- bases of 1- hydroxyl -1,3- dihydrobenzos [C] [1,2] oxa- boron) oxygen) benzonitrile is (shown in formula IV
Compound) preparation
By [5- (4- cyanophenoxies) -2- bromophenyl -1- methoxyl groups]-trimethyl silane 37.6g (0.1mol),
THF300ml is added in reaction kettle, under nitrogen protection, is cooled to -20 DEG C, 2.0mol/L isopropylmagnesium chloride tetrahydrochysene furans are added dropwise
It mutters solution (75ml, 0.15mol), temperature is no more than -10 DEG C, and 2h drops are about added dropwise and finish, and 20 DEG C are stirred 1h, solution for standby；
THF300ml, 23.7g (0.15mol) 2- methoxyl groups -4,4,5,5- tetramethyls -1,3,2- bis- are added in reaction bulb
Penta ring of oxygen boron, is cooled to 0-10 DEG C, and above-mentioned stock solution is added dropwise, and 2h is about added dropwise, and drop finishes, and salt is added in 25 DEG C of reaction 6h, ice bath
Acid reacts 5 hours for 3 hereinafter, being stirred at room temperature to pH value, recycles organic solvent, 0-10 DEG C of crystallization, and filtration drying obtains compound
18g, yield 72%；
1HNMR(500MHz,DMSO-d6)δppm 4.98(s,2H),7.13(dd,1H),7.23(d1H),7.43(d,
1H),7.35(d,1H),7.26(d,2H),9.19(s,1H).ESI M-H 250
The embodiment of the present invention is described above, above description is exemplary, and non-exclusive, and also not
It is limited to disclosed embodiment.Without departing from the scope and spirit of embodiment described, for the art
Those of ordinary skill for many modifications and changes will be apparent from.
Claims (7)
1. the preparation method of a kind of gram of vertical boron sieve, which is characterized in that the preparation method includes the following steps：
(1) in the presence of the first solvent, compound shown in formula I and alkali metal borohydride is subjected to haptoreaction, obtain formula
II compounds represented；
(2) in the presence of the second organic solvent and alkali, the Formula II compound represented and compound a contact anti-
It answers, obtains compound shown in formula III；Or in the presence of the second organic solvent and catalyst, by compound shown in the Formula II
Haptoreaction is carried out with dihydropyran, obtains compound shown in formula III；Wherein, the compound a is trim,ethylchlorosilane, tertiary fourth
Base dimethylchlorosilane or chloromethyl methyl ether；
Wherein, wherein R is trimethylsilyl, t-butyldimethylsilyi, dimethyl cellosolve base or THP trtrahydropyranyl；
(3) in the presence of third organic solvent and protective gas, compound shown in the formula III and isopropylmagnesium chloride is molten
Liquid carries out haptoreaction, obtains stock solution；Then the stock solution is added to the mixing of compound b and third organic solvent
Haptoreaction is carried out in liquid, adds hydrochloric acid haptoreaction, obtains gram vertical boron sieve, the compound as shown in formula IV；Wherein, describedization
It is penta ring of 2- alkoxy -4,4,5,5- tetramethyl -1,3,2- dioxies boron, triisopropyl borate ester or trimethylborate to close object b；
2. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (1), the alkali metal borohydride
Dosage is the 0.5-1 equivalents of compound shown in the formula I；The alkali metal borohydride is sodium borohydride and/or potassium borohydride；
First solvent is at least one of methanol, ethyl alcohol, isopropanol, water and tetrahydrofuran.
3. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (2), second organic solvent is two
Chloromethanes, tetrahydrofuran, at least one of toluene and n,N-Dimethylformamide；The alkali be organic base and/or inorganic base,
The organic base is at least one of triethylamine, tri-n-butylamine, diisopropylethylamine and imidazoles, and the inorganic base is sodium hydride,
Sodium hydroxide, potassium hydroxide, at least one of sodium carbonate and potassium carbonate；The catalyst is p-methyl benzenesulfonic acid.
4. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (3), by compound shown in the formula III
Carrying out catalytic reaction condition with isopropylmagnesium chloride solution includes：In the presence of protective gas, by the isopropyl chloride
It is -20- to change holding temperature during magnesium solution is added dropwise to compound shown in formula III and in the mixed liquor of third organic solvent, is added dropwise
0℃。
5. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (3), compound shown in formula IV
Reaction condition includes：The stock solution is added dropwise in the mixed liquor of the compound b and third organic solvent, it is described spare
Solution has added in 1-2h, and 0-25 DEG C of reaction 6-12h, then addition hydrochloric acid to pH value is 3 hereinafter, continuing anti-under condition of ice bath
Answer 3-7h.
6. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (3), the isopropylmagnesium chloride solution
In isopropylmagnesium chloride amount be the formula III shown in compound 1-2.5 equivalents；The dosage of the compound b is described standby
With the 1-2.5 equivalents of solution；The third organic solvent is tetrahydrofuran, ether, methyltetrahydrofuran and glycol dimethyl ether
At least one of.
7. the preparation method of gram vertical boron sieve according to claim 1, wherein in step (3), the 2- alkoxies -4,4,5,
Penta ring of 5- tetramethyl -1,3,2- dioxies boron is that penta ring of 2- methoxyl group -4,4,5,5- tetramethyl -1,3,2- dioxies boron and/or 2- are different
Penta ring of propane oxygroup -4,4,5,5- tetramethyl -1,3,2- dioxies boron.
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| CN110357792A (en) * | 2019-08-19 | 2019-10-22 | 武汉轻工大学 | A kind of preparation method of gram of vertical boron sieve intermediate |
| CN114933607A (en) * | 2022-04-29 | 2022-08-23 | 山东诺明康药物研究院有限公司 | Preparation method of 4-fluoro-2-hydroxymethyl phenylboronic acid and cliborole |
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