CN111978209B - Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline - Google Patents
Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline Download PDFInfo
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- YTMVYYAKOPIJCZ-UHFFFAOYSA-N 4-bromo-3-fluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1 YTMVYYAKOPIJCZ-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 24
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 101
- 238000000034 method Methods 0.000 claims abstract description 43
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229940125782 compound 2 Drugs 0.000 claims abstract description 17
- 229940126214 compound 3 Drugs 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- 239000007864 aqueous solution Substances 0.000 claims description 43
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 40
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 28
- 239000007787 solid Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 235000010288 sodium nitrite Nutrition 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 16
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 10
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 15
- 239000012535 impurity Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- RLMBRRQWBTWGMB-UHFFFAOYSA-N 4-amino-3-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1F RLMBRRQWBTWGMB-UHFFFAOYSA-N 0.000 description 12
- QBKXYSXQKRNVRQ-UHFFFAOYSA-N 4-bromo-3-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1Br QBKXYSXQKRNVRQ-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- BTBFCBQZFMQBNT-UHFFFAOYSA-N 3,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1F BTBFCBQZFMQBNT-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000005259 measurement Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 239000005489 Bromoxynil Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- ISAQGADJGBSNRH-UHFFFAOYSA-N 2,4-dibromo-5-fluoroaniline Chemical compound NC1=CC(F)=C(Br)C=C1Br ISAQGADJGBSNRH-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- FWTXFEKVHSFTDQ-UHFFFAOYSA-N 2-bromo-5-fluoroaniline Chemical compound NC1=CC(F)=CC=C1Br FWTXFEKVHSFTDQ-UHFFFAOYSA-N 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- NTWMKNSGFIRDSF-OAHLLOKOSA-N CN1N=NC(C(N=C2)=CC=C2C(C=CC(N(C[C@@H](OP(C)(O)=O)O2)C2=O)=C2)=C2F)=N1 Chemical compound CN1N=NC(C(N=C2)=CC=C2C(C=CC(N(C[C@@H](OP(C)(O)=O)O2)C2=O)=C2)=C2F)=N1 NTWMKNSGFIRDSF-OAHLLOKOSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthetic method of a tedizolid phosphate intermediate 3-fluoro-4-bromoaniline, which comprises the following steps: (1) reacting the compound 1 with ammonia gas to obtain a compound 2; (2) reacting compound 2 with hydrobromic acid to obtain compound 3; (3) The cyano group in compound 3 is reduced to an amino group to give compound 4. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple equipment requirements and high safety index, and is suitable for large-scale commercial production. The yield of the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate prepared by the process of the invention is up to more than 56.61 percent, the purity is up to more than 99.70 percent, and the content of isomer impurities in the product is as low as below 0.17 percent. The invention provides a cheap and easily obtained high-quality intermediate for the commercial production of the raw material medicine of the tedizolid phosphate, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a synthetic method of a tedizolid phosphate intermediate 3-fluoro-4-bromoaniline.
Background
Tertrazolamide phosphate is a novel oxazolidinone antibiotic developed by the company Cubist pharmaceutical under the chemical name { (5R) - (3- { 3-fluoro-4- [6- (2-methyl-2H-tetrazol-5-yl) -pyridin-3-yl ] phenyl } -2-oxooxazolidin-5-yl) } methylphosphonate. Approved by the FDA for clinical use in the treatment of acute bacterial skin and skin structure infections in 2014. Tertrazolamide phosphate is a prodrug that can be rapidly converted to tertrazolamide having biological activity by phosphatase in vivo, thereby inhibiting the synthesis of proteins.
The chemical structure of tedizolid phosphate is shown as follows:
the 3-fluoro-4-bromoaniline is an intermediate for preparing the tedizolid phosphate, and the chemical structure is shown as follows:
the literature Synthesis,2009, #8, art. No. p12608ss, p.1305-1308 and WO2014/202580 all report routes to two synthetic intermediates, 3-fluoro-4-bromoanilines. The first synthesis route is as follows:
the route takes 3-fluoroaniline as a starting material to synthesize 3-fluoro-4-bromoaniline. The major defects of the route are that the 2-bromo-5-fluoroaniline as a position isomer and a small amount of 2, 4-dibromo-5-fluoroaniline as a double-bromo-substituted compound can be generated in the second-step bromination reaction process, the purification difficulty of the two compounds is high, the total yield of the target product is low, and the impurity content is too high. Wherein the reaction process for producing the positional isomer impurity and the dibromo-substituted impurity is as follows:
the second synthetic route reported in this document has the same technical drawbacks as the first route. The inventor of the application carries out repeated pilot experiments on the synthetic routes reported in the above documents, and discovers that whether the route one or the route two is adopted, the content of the position isomer impurity in the target product is between 3 and 11 percent, and the quality requirement of the initial raw material of the raw material medicine for synthesizing the tedizolid phosphate can not be met. The experimental result also shows that if the content of the positional isomer impurity in the target product is purified from 3-11% to 0.1-0.5%, multiple times of purification are needed, and the total yield of the target product is lower than 35% after the multiple times of purification.
In addition, the synthesis method of 3-fluoro-4-bromoaniline is reported in literature, but the method does not provide a detailed process route, oxygen is required to be introduced when copper chloride is used for catalyzing reaction, so that the ignition and explosion are easily caused, and in addition, the synthesis process can only be carried out in a laboratory and cannot realize large-scale commercial production.
From the above, in order to promote the industrialized production of the raw material drug, namely, tedizolid phosphate, the intermediate 3-fluoro-4-bromoaniline must be first marketed and industrialized. Therefore, innovation of the synthesis process of 3-fluoro-4-bromoaniline is needed, and a process which is low in price, safe to operate and suitable for large-scale commercial production is developed to prepare the high-purity and high-yield terozolomide phosphate intermediate 3-fluoro-4-bromoaniline.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a process which is low in cost, safe to operate and suitable for large-scale commercial production, and the method is used for preparing the high-purity and high-yield tedizolid phosphate intermediate 3-fluoro-4-bromoaniline.
The invention provides a synthetic method of a tedizolid phosphate intermediate 3-fluoro-4-bromoaniline, which comprises the following steps:
(1) Reacting the compound 1 with ammonia gas to obtain a compound 2;
(2) Reacting the compound 2 with hydrobromic acid to obtain a compound 3;
(3) The cyano group in compound 3 is reduced to an amino group to give compound 4.
Further, in the step (1), the mass ratio of the compound 1 to the ammonia gas is (1.5-2.5): 1.0; the solvent of the reaction is an organic solvent; the volume mass ratio of the solvent to the compound 1 of the reaction is (2-1): 1mL/g; the reaction is carried out in a closed ammonia atmosphere; the reaction temperature is 70-90 ℃ and the reaction time is 16-32 hours.
Further, in the step (1), the mass ratio of the compound 1 to the ammonia gas is (1.7-2.0) 1.0; the solvent for the reaction is an alcohol solvent, preferably ethanol; the volume mass ratio of the solvent of the reaction to the compound 1 is 1:1mL/g; the reaction temperature is 80-90 ℃ and the reaction time is 24-26 hours.
Further, in the step (1), after the reaction is finished, the method further comprises the following steps: cooling the reaction system to-10 ℃, removing the reaction solvent, then adding ethyl acetate for dissolution, then adding water for washing, taking an organic phase, concentrating and drying;
preferably, the reaction system is cooled to-5 to 5 ℃, and the mass volume ratio of the compound 1 to the ethyl acetate to the water is 1g: (2-4) mL: (0.5-3) mL, preferably 1g:3mL: (0.7-1.5) mL.
Further, in the step (2), the hydrobromic acid is an aqueous hydrobromic acid solution with the mass fraction of 30% -50%, and the mass-volume ratio of the compound 2 to the aqueous hydrobromic acid solution is 1: (3.0-5.0) g/mL; the reaction is carried out in the presence of cuprous bromide and sodium nitrite, preferably, the sodium nitrite is sodium nitrite aqueous solution with the mass fraction of 20% -40%; the mass ratio of the compound 2 to the cuprous bromide to the sodium nitrite aqueous solution is 1: (0.3-0.8): (2.0 to 3.0); the reaction temperature is-10 ℃, and the reaction time is 3-6 hours.
Further, in the step (2), the hydrobromic acid aqueous solution is 40% by mass, and the mass-volume ratio of the compound 2 to the hydrobromic acid aqueous solution is 1: (3.5-4.5) g/mL; the sodium nitrite aqueous solution is 30% of sodium nitrite aqueous solution by mass, and the mass ratio of the compound 2 to the cuprous bromide to the sodium nitrite aqueous solution is 1:0.5:2.5; the reaction temperature is-5 ℃ and the reaction time is 4 hours.
Further, in the step (2), after the reaction is finished, the method further comprises the following steps: heating the reaction system to room temperature, adding water, stirring uniformly, filtering, and retaining solids; wherein the volume/mass ratio of the water to the compound 2 is preferably (5-30): 1mL/g, more preferably 15:1mL/g, and the stirring time is preferably 5-60 minutes, more preferably 10-20 minutes.
Further, the reaction process of the step (3) is as follows: the compound 3 and hydrogen peroxide react for 1 to 3 hours at the temperature of minus 10 to 10 ℃ in the presence of alkali, then a catalyst is added, the reaction is carried out for 2 to 6 hours at the temperature of minus 10 to 10 ℃, sodium hypochlorite is added, and the reaction is continued for 5 to 9 hours at the temperature of minus 10 to 10 ℃;
preferably, the alkali is inorganic alkali, the hydrogen peroxide is a hydrogen peroxide solution with the mass fraction of 20-40%, the catalyst is manganese dioxide, the sodium hypochlorite is a sodium chlorate aqueous solution with the mass fraction of 5-15%, and the solvent for the reaction is a mixed solution of an organic solvent and water, preferably a mixed solution of tetrahydrofuran and water; the mass volume ratio of the compound 3 to the hydrogen peroxide solution to the alkali to the catalyst to the sodium hypochlorite aqueous solution is 1g: (1.00-1.50) g: (0.10-0.50) g: (0.002-0.010) g: (8-15) mL.
Further, the reaction process of the step (3) is as follows: the compound 3 and hydrogen peroxide react for 2 hours at the temperature of minus 5 ℃ to 5 ℃ in the presence of alkali, then a catalyst is added, the reaction is carried out for 4 hours at the temperature of minus 5 ℃ to 5 ℃, sodium hypochlorite is added, and the reaction is continued for 6 hours to 8 hours at the temperature of minus 5 ℃ to 5 ℃;
the alkali is sodium hydroxide, the hydrogen peroxide solution is 27.5% of hydrogen peroxide solution by mass fraction, the sodium chlorate aqueous solution is 10% of sodium chlorate aqueous solution by mass fraction, and the volume ratio of tetrahydrofuran to water in the mixed solution of tetrahydrofuran and water is 1:2; the mass volume ratio of the compound 3 to the hydrogen peroxide solution to the alkali to the catalyst to the sodium hypochlorite aqueous solution is 1g:1.25g:0.24g:0.005g:11.25mL.
Further, in the step (3), after the reaction is finished, the method further comprises the following steps: filtering the reaction system, taking solid, adding ethyl acetate for dissolution, washing with saturated sodium chloride aqueous solution, taking organic phase for concentration, then adding n-hexane for dissolution, crystallizing, and retaining the precipitated solid;
preferably, the mass volume ratio of the compound 3 to the ethyl acetate to the saturated sodium chloride aqueous solution to the n-hexane is 1g: (3-5) mL: (0.3-1) mL: (0.7 to 1.3) mL, preferably 1g:4mL:0.5mL:1mL; the crystallization temperature is 0-5 ℃, and the crystallization time is 1 hour.
"40% hydrobromic acid" refers to an aqueous solution of hydrobromic acid having a mass fraction of 40%.
"30% sodium nitrite aqueous solution" means 30% sodium nitrite aqueous solution by mass fraction.
"27.5% hydrogen peroxide solution" refers to 27.5% hydrogen peroxide solution by mass fraction.
"10% aqueous sodium hypochlorite solution" refers to an aqueous sodium hypochlorite solution having a mass fraction of 10%.
"room temperature" means 25.+ -. 5 ℃.
Compared with the prior art, the method for preparing the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate has the following advantages:
1. the preparation process of the invention takes 3, 4-difluorobenzonitrile as the initial raw material, and the 3, 4-difluorobenzonitrile is cheap and easy to obtain in the market, thereby reducing the production cost; the method has the advantages of mild reaction conditions, simple equipment, simple process and easy operation, and is suitable for large-scale commercial production.
2. The preparation process effectively controls the generation of isomer impurities, and reduces the content of the isomer impurities to below 0.17%; meanwhile, the purification process is simple, the total yield of the target product is improved, and the total yield of the target product of the process can be stabilized to be more than 56% even in large-scale production.
3. N-bromosuccinimide (NBS) is not used in the reaction process, so that the generation of a large amount of organic byproducts, namely solid waste, is avoided, and the method is environment-friendly.
4. The reaction process of the invention does not need to introduce oxygen, thereby improving the safety coefficient and being beneficial to large-scale commercial production.
In a word, the process for preparing the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate provided by the invention has the advantages of low-cost and easily obtained raw materials, mild reaction conditions, simple equipment requirements and high safety index, and is suitable for large-scale commercial production. The yield of the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate prepared by the process can reach more than 56.61 percent, the purity can reach more than 99.70 percent, and the content of isomer impurities in the product is as low as below 0.17 percent, even as low as below 0.06 percent.
Therefore, the invention provides a cheap and easily obtained high-quality intermediate for the commercial production of the raw material medicine of the tedizolid phosphate, and has wide application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 HPLC chromatogram of 3-fluoro-4-bromoaniline obtained in example 1.
FIG. 2 is an HPLC chart of 3-fluoro-4-bromoaniline as the product obtained in example 2.
Detailed Description
The raw materials used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
EXAMPLE 1 Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline
(1) Synthesis of 3-fluoro-4-aminobenzonitrile
70g of raw material 3, 4-difluorobenzonitrile is added into a reaction kettle, 70mL of absolute ethyl alcohol is added, the reaction kettle is closed, 35g of ammonia gas is introduced once again after the air in the reaction kettle is replaced by ammonia gas, the temperature is raised to 80-90 ℃ for reaction for 24 hours, after the reaction is finished, the temperature is reduced to-5 ℃, the reactant is concentrated to remove the ethanol after pressure release, 200mL of ethyl acetate is added for dissolution, 50mL of water is used for washing, an organic phase is concentrated and dried, and the off-white solid 3-fluoro-4-aminobenzonitrile 58g is obtained, the purity is 99% by HPLC measurement, and the yield is 85%.
(2) Synthesis of 3-fluoro-4-bromoxynil
In a reaction kettle, 40.8g of 3-fluoro-4-aminobenzonitrile obtained in the step (1) is dissolved in 160ml of 40% hydrobromic acid, 21.6g of cuprous bromide is added, the mixture is cooled to-5 ℃, 100g of 30% sodium nitrite aqueous solution is dropwise added into a reaction system under stirring, the mixture is kept at-5 ℃ for stirring and reacting for 4 hours, then the mixture is naturally warmed to room temperature, 600ml of water is added, stirring is carried out for 10 minutes, and 54g of white solid 3-fluoro-4-bromobenzonitrile is obtained by filtering. Purity was 98.6% by HPLC and yield 90%.
(3) Synthesis of 3-fluoro-4-bromoaniline
In a reaction kettle, 40.0g of 3-fluoro-4-bromobenzonitrile obtained in the step (2) is dissolved in 80ml of tetrahydrofuran, 160ml of deionized water is added, the mixture is cooled to-5-0 ℃, 9.6g of sodium hydroxide is added, 50g of 27.5% hydrogen peroxide solution is slowly dripped into a reaction system under stirring, the mixture is kept at-5 ℃ for 2 hours, 0.2g of manganese dioxide catalyst is added to decompose excessive hydrogen peroxide, the mixture is stirred at-5 ℃ for 4 hours under heat preservation, and then 450ml of 10% sodium hypochlorite aqueous solution is slowly dripped into the reaction system under heat preservation and stirring for 8 hours under-5 ℃. After the reaction, 75g of a gray solid was obtained by filtration, and the gray solid was dissolved in 150mL of ethyl acetate, washed twice with 20mL of saturated aqueous sodium chloride solution, and the organic phase was concentrated, 50mL of n-hexane was added to the concentrate, and stirred, and crystallized at 0 to 5℃for 1 hour to obtain 28g of 3-fluoro-4-bromoaniline as a pale yellow powder solid in a yield of 74%.
The HPLC spectrum of the target product 3-fluoro-4-bromoaniline obtained in this example is shown in FIG. 1, and it can be seen that the purity of the 3-fluoro-4-bromoaniline in the obtained target product is 99.91%, and the isomer impurity content is 0.055%. The total yield of the process for synthesizing 3-fluoro-4-bromoaniline in this example is 56.61%.
Total yield = yield of step (1) x yield of step (2) x yield of step (3)
EXAMPLE 2 Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline
(1) Synthesis of 3-fluoro-4-aminobenzonitrile
140g of raw material 3, 4-difluorobenzonitrile is added into a reaction kettle, 150mL of absolute ethyl alcohol is added, the reaction kettle is closed, ammonia gas is introduced once again after the air in the reaction kettle is replaced by ammonia gas, the temperature is raised to 70-80 ℃ for reaction for 24 hours, after the reaction is finished, the temperature is reduced to-5 ℃, the pressure is released, the reactant is concentrated to remove the ethanol, 400mL of ethyl acetate is added for dissolution, 70mL of water is used for washing, the organic phase is concentrated and dried, and the white solid 3-fluoro-4-aminobenzonitrile 119g is obtained, the purity is 99% by HPLC measurement, and the yield is 87%.
(2) Synthesis of 3-fluoro-4-bromoxynil
In a reaction kettle, 82g of 3-fluoro-4-aminobenzonitrile obtained in the step (1) is dissolved in 300ml of 40% hydrobromic acid, 40g of cuprous bromide is added, cooling is carried out to-5 ℃,200 g of 30% sodium nitrite aqueous solution is dropwise added into a reaction system under stirring, stirring reaction is carried out for 4 hours at-5 ℃, 1200ml of water is added, stirring is carried out for 15 minutes, and 110g of white solid 3-fluoro-4-bromobenzonitrile is obtained after filtering. Purity by HPLC was 99% and yield 91%.
(3) Synthesis of 3-fluoro-4-bromoaniline
In a reaction kettle, 80g of 3-fluoro-4-bromobenzonitrile obtained in the step (2) is dissolved in 150ml of tetrahydrofuran, 300ml of deionized water is added, the mixture is cooled to-5-0 ℃,20 g of sodium hydroxide is added, 100g of 27.5% hydrogen peroxide solution is slowly added into a reaction system dropwise under stirring, the mixture is kept at-5 ℃ for 2 hours, 0.4g of manganese dioxide catalyst is added for decomposing excessive hydrogen peroxide, the mixture is kept at-5 ℃ for 4 hours under stirring, and then 1000ml of 10% sodium hypochlorite aqueous solution is slowly added into the reaction system dropwise under stirring at-5 ℃ for 8 hours. After the reaction, 158g of a gray solid was obtained by filtration, the gray solid was dissolved in 300mL of ethyl acetate, washed twice with 40mL of saturated aqueous sodium chloride solution, the organic phase was concentrated, 100mL of n-hexane was added to the concentrate, and the mixture was stirred and crystallized at 0 to 5℃for 1 hour to obtain 60g of 3-fluoro-4-bromoaniline as a pale yellow powder solid in 79% yield.
The HPLC spectrum of the target product 3-fluoro-4-bromoaniline obtained in this example is shown in FIG. 2, and it can be seen that the purity of the 3-fluoro-4-bromoaniline in the obtained target product is 99.85%, and the isomer impurity content is 0.119%. The total yield of the process for synthesizing 3-fluoro-4-bromoaniline of this example was 62.54%. Total yield = yield of step (1) x yield of step (2) x yield of step (3).
The product obtained in this example was subjected to hydrogen spectrum and mass spectrometry analysis, and the analysis results were as follows:
1 H NMR(400MHz,DMSO)：δ7.23(t,J＝8.4Hz,1H),δ6.48(dd,J＝11.7,2.3Hz,1H),δ6.36(dd,J＝8.5,2.3Hz,1H),δ5.62(s,2H)。
MS(ES):m/z＝190[M+H]+,192[M+H]+。
EXAMPLE 3 Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline
(1) Synthesis of 3-fluoro-4-aminobenzonitrile
350g of raw material 3, 4-difluorobenzonitrile is added into a reaction kettle, 350mL of absolute ethyl alcohol is added, the reaction kettle is closed, ammonia gas is filled again after the air in the reaction kettle is replaced by ammonia gas, 170g of ammonia gas is filled again, the temperature is raised to 85-90 ℃ for reaction for 26 hours, after the reaction is finished, the temperature is reduced to minus 5-5 ℃, the temperature is reduced to be 5 ℃ after the pressure is released, the reactant is concentrated to remove the ethanol, 1000mL of ethyl acetate is added for dissolution, 500mL of water is used for washing, the organic phase is concentrated and dried, and the off-white solid 3-fluoro-4-aminobenzonitrile 297g is obtained, the purity is 99 percent by HPLC measurement, and the yield is 87 percent.
(2) Synthesis of 3-fluoro-4-bromoxynil
In a reaction kettle, 200g of 3-fluoro-4-aminobenzonitrile obtained in the step (1) is dissolved in 900ml of 40% hydrobromic acid, 100g of cuprous bromide is added, cooling is carried out to-5-0 ℃, 500g of 30% sodium nitrite aqueous solution is dropwise added into a reaction system under stirring, stirring reaction is carried out for 5 hours at-5-0 ℃, 3000ml of water is added, stirring is carried out for 20 minutes, and 278g of white solid 3-fluoro-4-bromobenzonitrile is obtained after filtering. Purity by HPLC was 99% and yield 92%.
(3) Synthesis of 3-fluoro-4-bromoaniline
In a reaction kettle, 200g of 3-fluoro-4-bromobenzonitrile obtained in the step (2) is dissolved in 400ml of tetrahydrofuran, 800ml of deionized water is added, cooling is carried out to-5-0 ℃, 50g of sodium hydroxide is added, 250g of 27.5% hydrogen peroxide solution is slowly added into a reaction system dropwise under stirring, stirring is carried out for 3 hours at-5-0 ℃, 1g of manganese dioxide catalyst is added to decompose excessive hydrogen peroxide, stirring is carried out for 4 hours at-5-0 ℃, then 2000ml of 10% sodium hypochlorite aqueous solution is slowly added into the reaction system dropwise under stirring at-5-0 ℃ for 8 hours. After the reaction, 382g of a gray solid was obtained by filtration, the gray solid was dissolved in 800mL of ethyl acetate, washed twice with 100mL of saturated aqueous sodium chloride solution, the organic phase was concentrated, 200mL of n-hexane was added to the concentrate, and stirred, and crystallization was carried out at 0 to 5℃for 1 hour to obtain 144g of 3-fluoro-4-bromoaniline as a pale yellow powder solid, with a yield of 76%. The HPLC measurement shows that the purity of 3-fluoro-4-bromoaniline in the target product obtained in this example is 99.88%, the content of isomer impurity is 0.090%, and the total yield of the process for synthesizing 3-fluoro-4-bromoaniline in this example is 60.83%. Total yield = yield of step (1) x yield of step (2) x yield of step (3).
EXAMPLE 4 Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline
(1) Synthesis of 3-fluoro-4-aminobenzonitrile
Adding 7kg of raw material 3, 4-difluorobenzonitrile into a reaction kettle, adding 7L of absolute ethyl alcohol, sealing, replacing air in the reaction kettle with ammonia gas, then introducing ammonia gas for 3.5kg again, heating to 80-90 ℃ for reaction for 24 hours, cooling to-5 ℃ after the reaction is finished, decompressing, concentrating the reactant to remove the ethanol, adding 20L of ethyl acetate for dissolving, washing with 10L of water, concentrating and drying an organic phase to obtain white-like solid 3-fluoro-4-aminobenzonitrile 5.92g, and measuring purity by HPLC to 99%, and yield to 86.8%.
(2) Synthesis of 3-fluoro-4-bromoxynil
In a reaction kettle, 4kg of 3-fluoro-4-aminobenzonitrile obtained in the step (1) is dissolved in 16L of 40% hydrobromic acid, 2.1kg of cuprous bromide is added, the mixture is cooled to-5 ℃, 10kg of 30% sodium nitrite aqueous solution is dropwise added into a reaction system under stirring, the mixture is kept at-5 ℃ for stirring and reacting for 4 hours, then the mixture is naturally warmed to room temperature, 60L of water is added, stirring is carried out for 20 minutes, and 5.6kg of white solid 3-fluoro-4-bromobenzonitrile is obtained by filtering. Purity by HPLC was 99% and yield 88%.
(3) Synthesis of 3-fluoro-4-bromoaniline
In a reaction kettle, 4kg of 3-fluoro-4-bromobenzonitrile obtained in the step (2) is dissolved in 8L of tetrahydrofuran, 15L of deionized water is added, the mixture is cooled to-5-0 ℃, 1kg of sodium hydroxide is added, 5kg of 27.5% hydrogen peroxide solution is slowly dripped into a reaction system under stirring, the temperature of-5 ℃ is kept and stirred for 2 hours, 200g of manganese dioxide catalyst is added to decompose excessive hydrogen peroxide, the mixture is kept and stirred for 4 hours at-5 ℃, and then 40L of 10% sodium hypochlorite aqueous solution is slowly dripped into the reaction system under heat preservation and stirring for 8 hours at-5 ℃. After the reaction, 8kg of a gray solid was obtained by filtration, the solid was dissolved in 15L of ethyl acetate, washed twice with 2L of saturated sodium chloride aqueous solution, the organic phase was concentrated, 5L of n-hexane was added to the concentrate, and stirred, and crystallization was carried out at 0 to 5℃for 1 hour to obtain 3.0kg of 3-fluoro-4-bromoaniline as a pale yellow powder solid, with a yield of 79%.
The HPLC measurement shows that the purity of 3-fluoro-4-bromoaniline in the target product obtained in this example is 99.70%, the content of isomer impurity is 0.17%, and the total yield of the process for synthesizing 3-fluoro-4-bromoaniline in this example is 60.34%. Total yield = yield of step (1) x yield of step (2) x yield of step (3).
In conclusion, the invention provides the method for preparing the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate, which has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple equipment requirements and high safety index, and is suitable for large-scale commercial production. The yield of the intermediate 3-fluoro-4-bromoaniline of the tedizolid phosphate prepared by the process of the invention is up to more than 56.61 percent, the purity is up to more than 99.70 percent, and the content of isomer impurities in the product is as low as below 0.17 percent. The invention provides a cheap and easily obtained high-quality intermediate for the commercial production of the raw material medicine of the tedizolid phosphate, and has wide application prospect.
Claims (14)
1. A synthetic method of a tedizolid phosphate intermediate 3-fluoro-4-bromoaniline is characterized in that: the method comprises the following steps:
(1) Reacting the compound 1 with ammonia gas to obtain a compound 2; the mass ratio of the compound 1 to the ammonia gas is (1.5-2.5) 1.0, the solvent of the reaction is ethanol, the reaction is carried out in a closed ammonia gas atmosphere, the temperature of the reaction is 70-90 ℃, and the reaction time is 16-32 hours; after the reaction is finished, the method further comprises the following steps: cooling the reaction system to-10 ℃, removing the reaction solvent, then adding ethyl acetate for dissolution, then adding water for washing, taking an organic phase, concentrating and drying;
(2) Reacting the compound 2 with hydrobromic acid to obtain a compound 3; the reaction is carried out in the presence of cuprous bromide and sodium nitrite, wherein the sodium nitrite is sodium nitrite aqueous solution with the mass fraction of 20% -40%, and the mass ratio of the compound 2 to the cuprous bromide to the sodium nitrite aqueous solution is 1: (0.3-0.8): (2.0-3.0), wherein the reaction temperature is-10 ℃, and the reaction time is 3-6 hours; after the reaction is finished, the method further comprises the following steps: heating the reaction system to room temperature, adding water, stirring uniformly, filtering, and retaining solids;
(3) The cyano group in compound 3 is reduced to an amino group to give compound 4; the reaction process of the step (3) is as follows: the compound 3 and hydrogen peroxide react for 1 to 3 hours at the temperature of minus 10 to 10 ℃ in the presence of alkali, then a catalyst is added, the reaction is carried out for 2 to 6 hours at the temperature of minus 10 to 10 ℃, sodium hypochlorite is added, and the reaction is continued for 5 to 9 hours at the temperature of minus 10 to 10 ℃; after the reaction is finished, the method further comprises the following steps: filtering the reaction system, taking solid, adding ethyl acetate for dissolution, washing with saturated sodium chloride aqueous solution, taking organic phase for concentration, then adding n-hexane for dissolution, crystallizing, and retaining the precipitated solid.
2. The method according to claim 1, characterized in that: in the step (1), the volume mass ratio of the solvent to the compound 1 in the reaction is (2-1): 1mL/g.
3. The method according to claim 2, characterized in that: in the step (1), the mass ratio of the compound 1 to the ammonia gas is (1.7-2.0) 1.0; the volume mass ratio of the solvent of the reaction to the compound 1 is 1:1mL/g; the reaction temperature is 80-90 ℃ and the reaction time is 24-26 hours.
4. The method according to claim 1, characterized in that: in the step (1), the reaction system is cooled to-5 ℃, and the mass volume ratio of the compound 1 to the ethyl acetate to the water is 1g: (2-4) mL: (0.5-3) mL.
5. The method according to claim 4, wherein: in the step (1), the mass-volume ratio of the compound 1 to the ethyl acetate to the water is 1g:3mL: (0.7-1.5) mL.
6. The method according to claim 1, characterized in that: in the step (2), hydrobromic acid is hydrobromic acid aqueous solution with the mass fraction of 30-50%, and the mass-volume ratio of the compound 2 to the hydrobromic acid aqueous solution is 1: (3.0-5.0) g/mL.
7. The method according to claim 6, wherein: in the step (2), the hydrobromic acid aqueous solution is 40% by mass, and the mass-volume ratio of the compound 2 to the hydrobromic acid aqueous solution is 1: (3.5-4.5) g/mL; the sodium nitrite aqueous solution is 30% of sodium nitrite aqueous solution by mass, and the mass ratio of the compound 2 to the cuprous bromide to the sodium nitrite aqueous solution is 1:0.5:2.5; the reaction temperature is-5 ℃ and the reaction time is 4 hours.
8. The method according to claim 1, characterized in that: in the step (2), the volume-mass ratio of the water to the compound 2 is (5-30) 1mL/g, and the stirring time is 5-60 minutes.
9. The method according to claim 8, wherein: in the step (2), the volume-mass ratio of the water to the compound 2 is 15:1mL/g, and the stirring time is 10-20 minutes.
10. The method according to any one of claims 1 to 9, characterized in that: in the step (3), the alkali is inorganic alkali, the hydrogen peroxide is a hydrogen peroxide solution with the mass fraction of 20-40%, the catalyst is manganese dioxide, the sodium hypochlorite is a sodium chlorate aqueous solution with the mass fraction of 5-15%, and the solvent for the reaction is a mixed solution of an organic solvent and water; the mass volume ratio of the compound 3 to the hydrogen peroxide solution to the alkali to the catalyst to the sodium hypochlorite aqueous solution is 1g: (1.00-1.50) g: (0.10-0.50) g: (0.002-0.010) g: (8-15) mL.
11. The method according to claim 10, wherein: the solvent for the reaction is a mixed solution of tetrahydrofuran and water.
12. The method according to claim 11, wherein: the reaction process of the step (3) is as follows: the compound 3 and hydrogen peroxide react for 2 hours at the temperature of minus 5 ℃ to 5 ℃ in the presence of alkali, then a catalyst is added, the reaction is carried out for 4 hours at the temperature of minus 5 ℃ to 5 ℃, sodium hypochlorite is added, and the reaction is continued for 6 hours to 8 hours at the temperature of minus 5 ℃ to 5 ℃;
the alkali is sodium hydroxide, the hydrogen peroxide solution is 27.5% of hydrogen peroxide solution by mass fraction, the sodium chlorate aqueous solution is 10% of sodium chlorate aqueous solution by mass fraction, and the volume ratio of tetrahydrofuran to water in the mixed solution of tetrahydrofuran and water is 1:2; the mass volume ratio of the compound 3 to the hydrogen peroxide solution to the alkali to the catalyst to the sodium hypochlorite aqueous solution is 1g:1.25g:0.24g:0.005g:11.25mL.
13. The method according to claim 12, wherein: in the step (3), the mass volume ratio of the compound 3 to the ethyl acetate to the saturated sodium chloride aqueous solution to the n-hexane is 1g: (3-5) mL: (0.3-1) mL: (0.7-1.3) mL; the crystallization temperature is 0-5 ℃, and the crystallization time is 1 hour.
14. The method according to claim 13, wherein: in the step (3), the mass volume ratio of the compound 3 to the ethyl acetate to the saturated sodium chloride aqueous solution to the n-hexane is 1g:4mL:0.5mL:1mL.
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| CN102993022A (en) * | 2011-09-14 | 2013-03-27 | 上海工程技术大学 | Preparation method of bromoaniline |
| CN109415359A (en) * | 2016-04-08 | 2019-03-01 | 人类制药有限公司 | Heterocycle GPR119 agonist compound |
| CN109678741A (en) * | 2019-01-29 | 2019-04-26 | 金凯(辽宁)化工有限公司 | The preparation method of 4- amino -3- fluobenzoic acid |
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| CN102993022A (en) * | 2011-09-14 | 2013-03-27 | 上海工程技术大学 | Preparation method of bromoaniline |
| CN109415359A (en) * | 2016-04-08 | 2019-03-01 | 人类制药有限公司 | Heterocycle GPR119 agonist compound |
| CN109678741A (en) * | 2019-01-29 | 2019-04-26 | 金凯(辽宁)化工有限公司 | The preparation method of 4- amino -3- fluobenzoic acid |
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Application publication date: 20201124 Assignee: Sichuan meiyugao Biomedical Technology Co.,Ltd. Assignor: CHENGDU MIRACLE PHARMACEUTICAL CO.,LTD. Contract record no.: X2023980054100 Denomination of invention: A synthetic method for intermediate 3-fluoro-4-bromoaniline of terazolamide phosphate Granted publication date: 20230530 License type: Common License Record date: 20231227 |