CN108911997A - A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol - Google Patents
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol Download PDFInfo
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- CN108911997A CN108911997A CN201810862895.8A CN201810862895A CN108911997A CN 108911997 A CN108911997 A CN 108911997A CN 201810862895 A CN201810862895 A CN 201810862895A CN 108911997 A CN108911997 A CN 108911997A
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- MNPLTKHJEAFOCA-UHFFFAOYSA-N 4-amino-3-fluorophenol Chemical compound NC1=CC=C(O)C=C1F MNPLTKHJEAFOCA-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 239000000843 powder Substances 0.000 claims abstract description 85
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 27
- 239000002131 composite material Substances 0.000 claims abstract description 26
- CSSGKHVRDGATJL-UHFFFAOYSA-N 3-fluoro-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C(F)=C1 CSSGKHVRDGATJL-UHFFFAOYSA-N 0.000 claims abstract description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000006185 dispersion Substances 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 67
- 238000006243 chemical reaction Methods 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 32
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 32
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 32
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 32
- 239000005642 Oleic acid Substances 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 32
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 32
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 32
- 229960004756 ethanol Drugs 0.000 claims description 25
- 235000019441 ethanol Nutrition 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 230000001376 precipitating effect Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 238000009210 therapy by ultrasound Methods 0.000 claims description 2
- 229910004298 SiO 2 Inorganic materials 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims 1
- 235000012239 silicon dioxide Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 238000000227 grinding Methods 0.000 description 8
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 7
- 229910052710 silicon Inorganic materials 0.000 description 7
- 239000010703 silicon Substances 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- -1 fluorobenzene Amine Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- QOZLOYKAFDTQNU-UHFFFAOYSA-N 2-amino-3-fluorophenol Chemical compound NC1=C(O)C=CC=C1F QOZLOYKAFDTQNU-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000219991 Lythraceae Species 0.000 description 1
- 235000014360 Punica granatum Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a kind of preparation methods of medicine intermediate 4- amino -3- fluorophenol, specifically include following steps：Modified granatum powder is prepared by raw material of granatum first, is then hydrolyzed in the dispersion liquid of modified granatum powder by ethyl orthosilicate, and the powder after hydrolysis is calcined, hollow silica powder is made；Then it is mixed to prepare composite catalyst with zinc powder；It finally using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, is reacted using pressurized with hydrogen, prepares target product 4- amino -3- fluorophenol.This method process is simple, and the catalyst of use is cheap, product purity and high income.
Description
Technical field：
The present invention relates to the preparation fields of medicine intermediate, are specifically related to a kind of medicine intermediate 4- amino -3- fluorobenzene
The preparation method of phenol.
Background technique：
4- amino -3- fluorophenol is the important intermediate of medicine, chemical industry preparation, and preparation method report is less, and the U.S. is learned
Person Benner, Brown etc., Derrenbacker etc., and Japanese scholars Tanaka etc., this grade of tall building are catalyzed with platinum carbon respectively, are carried out
It restores rearrangement reaction and 4- amino -3- fluorophenol is made.It since the technique easily leads to platinum carbon poisoning, is allowed to not apply, and causes
Production cost is excessively high.For Klausener etc. with o-fluoronitrobenzene, aqueous sulfuric acid is raw material, is catalyzed with platinum charcoal, using pressurized with hydrogen
Reaction, prepares fine work 4- amino -3- fluorophenol by porous extractor extraction.The technique solves the problems, such as platinum carbon recovery,
But it can not industrialized production due to using porous extractor.
Chinese patent (201610228793.1) discloses 4- amino -3- fluorophenol and its synthetic method, with a fluorobenzene
Amine is raw material, first progress diazo-reaction, then carries out fluorine solution reaction, white diazosalt solid is obtained, then to white diazonium
Reaction is hydrolyzed in salt solid, and m fluorophenol is made, finally carries out nitration reaction, reduction reaction again, and target product 4- is made
Amino -3- fluorophenol.Although this method product yield is high, the more verbose complexity of reaction process.
Summary of the invention：
The object of the present invention is to provide a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, the present invention is disclosed
Method reaction process it is simple, product yield is high, and low energy consumption.
To achieve the above object, the present invention uses following technical scheme：
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, ultrasonic at 35-45 DEG C
1-2h, after treatment are handled, modified granatum powder is made in centrifugal treating after precipitating drying；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 15-20h at 120-150 DEG C and is cooled to room temperature after reaction, filters, solid is done
It is dry, and in Muffle furnace, 30-50min is handled under air atmosphere at 500-800 DEG C, after treatment cools to room temperature with the furnace, system
Obtain hollow silica powder；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol.
As a preferred embodiment of the above technical solution, in step (1), the mass concentration of the sodium hydroxide solution is 20-40%.
As a preferred embodiment of the above technical solution, in step (1), the powder, oleic acid mass ratio be 1：(0.001-
0.005)。
As a preferred embodiment of the above technical solution, in step (1), the power of the ultrasonic treatment is 500-1000W.
As a preferred embodiment of the above technical solution, in step (2), the modified granatum powder, ethyl alcohol, ethyl orthosilicate, three
The amount ratio of ethamine is 1g：(20-50)mL：1mL：1mL.
As a preferred embodiment of the above technical solution, in step (4), the dosage of the composite catalyst is the fluoro- 4- nitrobenzene of 3-
The 0.1%-0.3% of phenol quality.
As a preferred embodiment of the above technical solution, in step (4), the temperature of the reaction is 80-120 DEG C, pressure 3-
5MPa。
As a preferred embodiment of the above technical solution, in step (3), hollow silica powder, zinc powder, oleic acid mass ratio be
1：(2-6)：0.02.
The invention has the advantages that：
Target product 4- amino -3- fluorine is made using 3- fluoro-4-nitrophenol as raw material, by catalytic hydrogenation reaction in the present invention
Phenol, the reaction process is simple, and the catalyst used is impregnated using lye first using granatum as raw material, handles colloid
Equal magazines, are then dispersed in the ethanol solution of oleic acid, and the modified granatum powder of oleic acid is made, is then dispersed in preparation two
In the reaction solution of silica, by teos hydrolysis, silica is made on Pomegranate Rind surface, finally in air
It is sintered under atmosphere and hollow silica is made, then it is made with zinc powder mixed grinding, calcium catalyst catalytic activity is high, preparation
It is at low cost；
The conversion ratio of method 3- fluoro-4-nitrophenol disclosed by the invention is 98% or more, and the yield of product is up to
95.2%.
Specific embodiment：
In order to better understand the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
The present invention is released, any restriction will not be constituted to the present invention.
Embodiment 1
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 500W function
1h, after treatment are ultrasonically treated under rate, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder, oleic acid
Mass ratio be 1：0.001；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 15h at 120 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 30min is handled at lower 500 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：20mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：2：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.1%；The temperature of the reaction is 80 DEG C, pressure 3MPa.
Embodiment 2
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 1000W
1-2h, after treatment are ultrasonically treated under power, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder,
The mass ratio of oleic acid is 1：0.005；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 20h at 150 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 50min is handled at lower 800 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：50mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：6：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.3%；The temperature of the reaction is 120 DEG C, pressure 5MPa.
Embodiment 3
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 600W function
1.5h, after treatment are ultrasonically treated under rate, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder, oil
The mass ratio of acid is 1：0.002；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 16h at 130 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 35min is handled at lower 550 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：30mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：3：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.15%；The temperature of the reaction is 90 DEG C, pressure 3.5MPa.
Embodiment 4
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 700W function
1.5h, after treatment are ultrasonically treated under rate, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder, oil
The mass ratio of acid is 1：0.003；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 17h at 130 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 40min is handled at lower 600 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：30mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：4：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.2%；The temperature of the reaction is 100 DEG C, pressure 4MPa.
Embodiment 5
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 800W function
1h, after treatment are ultrasonically treated under rate, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder, oleic acid
Mass ratio be 1：0.004；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 18h at 140 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 40min is handled at lower 650 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：30mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：5：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.2%；The temperature of the reaction is 110 DEG C, pressure 4MPa.
Embodiment 6
A kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, includes the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, so
After adopt and be washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, 35-45 DEG C, 900W function
2h, after treatment are ultrasonically treated under rate, modified granatum powder is made in centrifugal treating after precipitating drying；Wherein, powder, oleic acid
Mass ratio be 1：0.005；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicon is added dropwise into dispersion liquid
Acetoacetic ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, triethylamine is added into three-necked flask, and be passed through
Band water nitrogen, is warming up to back flow reaction 19h at 140 DEG C and is cooled to room temperature after reaction, filters, and solid is dry, and
In Muffle furnace, 30min is handled at lower 700 DEG C of air atmosphere, after treatment cools to room temperature with the furnace, and hollow silica is made
Powder；Wherein, modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：40mL：1mL：1mL；
(3) dehydrated alcohol is added after mixing hollow silica powder obtained above, zinc powder, oleic acid carries out at grinding
Composite catalyst is made in reason；Wherein, hollow silica powder, zinc powder, oleic acid mass ratio be 1：5.5：0.02；
(4) using 3- fluoro-4-nitrophenol as raw material, under the catalysis of composite catalyst obtained above, using hydrogen plus
Pressure reaction, prepares target product 4- amino -3- fluorophenol；Wherein, the dosage of composite catalyst is 3- fluoro-4-nitrophenol quality
0.2%；The temperature of the reaction is 110 DEG C, pressure 4.5MPa.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol, which is characterized in that include the following steps：
(1) granatum is shredded, is baked, then ground and powder is made；Powder is impregnated into 3h using sodium hydroxide solution, is then adopted
It is washed with deionized to neutrality, drying, powder obtained is scattered in the ethanol solution of oleic acid, is ultrasonically treated at 35-45 DEG C
Modified granatum powder is made in 1-2h, after treatment, centrifugal treating after precipitating drying；
(2) it disperses modified granatum powder obtained above in ethyl alcohol, dispersion liquid is made；Positive silicic acid second is added dropwise into dispersion liquid
Ester stirs and reaction solution is made, and places reaction liquid into three-necked flask, and triethylamine is added into three-necked flask, and is passed through band water
Nitrogen is warming up to back flow reaction 15-20h at 120-150 DEG C and is cooled to room temperature after reaction, filtering, and solid is dry, and
In Muffle furnace, 30-50min is handled under air atmosphere at 500-800 DEG C, after treatment cools to room temperature with the furnace, be made in
Empty SiO 2 powder；
(3) addition dehydrated alcohol, oleic acid are ground after mixing hollow silica powder obtained above, zinc powder,
Composite catalyst is made；
(4) anti-using pressurized with hydrogen under the catalysis of composite catalyst obtained above using 3- fluoro-4-nitrophenol as raw material
It answers, prepares target product 4- amino -3- fluorophenol.
2. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (1), the mass concentration of the sodium hydroxide solution is 20-40%.
3. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (1), the powder, oleic acid mass ratio be 1：(0.001-0.005).
4. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (1), the power of the ultrasonic treatment is 500-1000W.
5. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (2), the modified granatum powder, ethyl alcohol, ethyl orthosilicate, triethylamine amount ratio be 1g：(20-50)mL：1mL：
1mL。
6. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (4), the dosage of the composite catalyst is the 0.1%-0.3% of 3- fluoro-4-nitrophenol quality.
7. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (4), the temperature of the reaction is 80-120 DEG C, pressure 3-5MPa.
8. a kind of preparation method of medicine intermediate 4- amino -3- fluorophenol as described in claim 1, it is characterised in that：Step
Suddenly in (3), hollow silica powder, zinc powder, oleic acid mass ratio be 1：(2-6)：0.02.
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| CN103739505A (en) * | 2014-01-14 | 2014-04-23 | 新泰昊原化工有限责任公司 | Process for preparing ortho-aminophenol by virtue of continuous catalytic hydrogenation |
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| CN104250226A (en) * | 2013-06-27 | 2014-12-31 | 爱康药业有限公司 | Method for preparing regorafenib intermediate |
| CN103739505A (en) * | 2014-01-14 | 2014-04-23 | 新泰昊原化工有限责任公司 | Process for preparing ortho-aminophenol by virtue of continuous catalytic hydrogenation |
| CN108047064A (en) * | 2017-11-06 | 2018-05-18 | 中国科学院兰州化学物理研究所 | A kind of method that paranitroanisole catalytic hydrogenation prepares paraphenetidine |
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| 周壮 等: "用Pd-Fe/SiO2常压催化加氢合成3-氟-4-氨基苯酚的研究", 《淮阴师范学院学报（自然科学版）》 * |
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Application publication date: 20181130 |