CN113912499A - 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester - Google Patents
4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester Download PDFInfo
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- IWYPVZJXNKHKRF-UHFFFAOYSA-N methyl 4-fluoro-5-hydroxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(F)C=C1[N+]([O-])=O IWYPVZJXNKHKRF-UHFFFAOYSA-N 0.000 title claims abstract description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 66
- XEQZNNJOVGASTE-UHFFFAOYSA-N 4-fluoro-5-hydroxy-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC(O)=C(F)C=C1[N+]([O-])=O XEQZNNJOVGASTE-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000002808 molecular sieve Substances 0.000 claims abstract description 49
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000005886 esterification reaction Methods 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- HGGRAOYTQNFGGN-UHFFFAOYSA-N 4,5-difluoro-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1[N+]([O-])=O HGGRAOYTQNFGGN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 16
- 239000002798 polar solvent Substances 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 238000000605 extraction Methods 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000012295 chemical reaction liquid Substances 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000002390 rotary evaporation Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000001354 calcination Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 4
- 239000000292 calcium oxide Substances 0.000 description 4
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000000746 purification Methods 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, belonging to the technical field of organic synthesis. The preparation method comprises the following steps: (1) mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent for substitution reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid; (2) mixing the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst, and carrying out esterification reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester obtained by the method provided by the invention has high yield and purity, and is suitable for industrial production. The results of the examples show that the yield of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester obtained by the preparation method is 87.5-90% and the purity is 98.2-99.1%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester.
Background
4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester (C)8H6FNO5) Is an organic intermediate with wide application, and is mainly used in the pharmaceutical and dye industries. Currently, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate is less commercially available, and there is an urgent need for a new, efficient, green process for the preparation of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate.
In the traditional preparation process of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, concentrated sulfuric acid, phosphoric acid and p-toluenesulfonic acid are mostly adopted as catalysts to prepare the final product. Although the method has higher catalytic activity and is cheap and easy to obtain, the method has the defects of more side reactions, serious corrosion to equipment, high energy consumption, complex treatment of reaction waste liquid and the like, is only suitable for synthesis of a small amount, and is not suitable for large-scale production. Therefore, it is of great importance to develop a relevant synthesis process with easily available raw materials, few synthesis steps, easy product separation and purification, high yield, short reaction time and little pollution to the environment.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, the method is green and environment-friendly, the yield and the purity of the obtained 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester are high, and the method is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, which comprises the following steps:
(1) mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent for substitution reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid;
(2) mixing the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst, and carrying out esterification reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester.
Preferably, the inorganic strong base is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and rubidium hydroxide.
Preferably, the molar ratio of the 4, 5-difluoro-2-nitrobenzoic acid to the inorganic strong base is 1 (2-5).
Preferably, the temperature of the substitution reaction is 60-100 ℃, and the time is 20-60 min.
Preferably, the polar solvent is one or more of methanol, ethanol, diethyl ether, chloroform and acetone.
Preferably, the molecular sieve catalyst is one or more of a 3A molecular sieve, a 4A molecular sieve, a 5A molecular sieve, an NKF-5-80W molecular sieve, an NKF-6-25 molecular sieve and an NKF-7SC molecular sieve.
Preferably, the mass of the molecular sieve catalyst is 20-80% of that of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid.
Preferably, the volume ratio of the mass of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid to the volume of the methanol is 1g (1-5) mL.
Preferably, the esterification reaction is carried out at the temperature of 60-90 ℃ for 10-24 h.
Preferably, after the esterification reaction, the method further comprises post-treating the obtained esterification reaction liquid, wherein the post-treating comprises the following steps:
and carrying out solid-liquid separation on the esterification reaction liquid, and sequentially carrying out organic extraction, drying, extractant removal and recrystallization on the obtained liquid to obtain a pure 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester product.
The invention provides a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, which comprises the following steps: (1) mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent for substitution reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid; (2) mixing the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst, and carrying out esterification reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The invention uses inorganic strong base as electron donor, because the para-position carbon of nitro group on benzene ring is most electron deficient, and has noWhen the organic alkaline agent reacts, the organic alkaline agent is easy to be subjected to OH-Attack of (2) by nucleophilic substitution, F in position 5-Is covered with OH-Substitution to generate 4-fluoro-5-hydroxy-2-nitrobenzoic acid; the method takes the molecular sieve as the catalyst for the esterification reaction of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid and the methanol, and has low cost; the molecular sieve is a solid-phase catalyst, can be well separated from the esterification reaction liquid and recycled, simplifies the treatment process of the esterification reaction liquid, and is green and environment-friendly. The 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester obtained by the method provided by the invention has higher yield and purity, and is suitable for industrial production. The results of the examples show that the yield of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester obtained by the preparation method is 87.5-90% and the purity is 98.2-99.1%.
Drawings
FIG. 1 shows the preparation of 4-fluoro-5-hydroxy-2-nitrobenzoic acid from example 11H-NMR chart;
FIG. 2 is a drawing showing methyl 4-fluoro-5-hydroxy-2-nitrobenzoate obtained in example 11H-NMR chart.
Detailed Description
The invention provides a preparation method of 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester, which comprises the following steps:
(1) mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent for substitution reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid;
(2) mixing the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst, and carrying out esterification reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester.
The method comprises the steps of mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent, and carrying out substitution reaction to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. In the invention, the inorganic strong base is preferably one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and rubidium hydroxide. In the invention, the molar ratio of the 4, 5-difluoro-2-nitrobenzoic acid to the inorganic strong base is preferably 1 (2-5), and more preferably 1 (2.5-4).
In the present invention, the polar solvent is preferably one or more of methanol, ethanol, diethyl ether, chloroform and acetone. In the invention, the ratio of the mass of the 4, 5-difluoro-2-nitrobenzoic acid to the volume of the solvent is preferably 1g (1-3) mL, and more preferably 1g (1.5-2.5) mL.
In the present invention, the mixing is preferably: firstly, mixing 4, 5-difluoro-2-nitrobenzoic acid with a polar solvent, and then adding inorganic strong base. In the present invention, the mixing is preferably performed under stirring.
In the invention, the reaction temperature of the substitution reaction is preferably 60-100 ℃, and more preferably 70-100 ℃; the reaction time is preferably 20 to 60min, and more preferably 25 to 50 min. The substitution reaction is preferably carried out under the condition of stirring, and the specific implementation process of the stirring is not particularly required by the invention. In the invention, because the para-position carbon of the nitro group on the benzene ring is most electron-deficient, the benzene ring is easily subjected to OH when reacting with an inorganic alkaline agent-Attack of (2) by nucleophilic substitution, F in position 5-Is covered with OH-And 4-fluoro-5-hydroxy-2-nitrobenzoic acid is generated by substitution.
After the substitution reaction, the present invention preferably performs a post-treatment of the obtained substitution reaction liquid, and in the present invention, the post-treatment preferably includes the steps of:
and adjusting the pH value of the substitution reaction liquid to 1-3, performing organic extraction on the substitution reaction liquid, drying an extraction phase, removing an extracting agent, and recrystallizing to obtain a pure 4-fluoro-5-hydroxy-2-nitrobenzoic acid product.
In the invention, the regulator for adjusting the pH value is preferably a hydrochloric acid solution, and the invention has no special requirement on the mass concentration of the hydrochloric acid solution.
In the invention, the extractant for extraction is preferably ethyl acetate, the volume ratio of the extractant to the substitution reaction liquid after the pH value is adjusted is preferably 1:1, and the target product 4-fluoro-5-hydroxy-2-nitrobenzoic acid is preferably extracted into an extraction phase by extraction.
In the present invention, the drying desiccant is preferably one or more of anhydrous sodium sulfate, solid calcium oxide, anhydrous calcium chloride, anhydrous potassium carbonate, and anhydrous magnesium sulfate.
In the present invention, the extraction agent is preferably removed by rotary evaporation. In the invention, the rotary evaporation temperature is preferably 35-45 ℃, and the rotary evaporation time is not specially required so as to remove the extractant cleanly.
In the invention, the solvent used for recrystallization is preferably a mixed solvent of toluene and cyclohexane, the volume ratio of toluene and cyclohexane is preferably 1:1, the mass ratio of the solid product of the rotary product and the mixed solvent is preferably 1:1, and the invention has no special requirements on the specific implementation process of recrystallization.
After the 4-fluoro-5-hydroxy-2-nitrobenzoic acid is obtained, the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst are mixed for esterification reaction to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. In the invention, the molecular sieve catalyst is preferably one or more of a 3A molecular sieve, a 4A molecular sieve, a 5A molecular sieve, an NKF-5-80W molecular sieve, an NKF-6-25 molecular sieve and an NKF-7SC molecular sieve. In the invention, the particle size of the molecular sieve catalyst is preferably 3-5 mm.
In the invention, the mass of the molecular sieve catalyst is preferably 20-80% of that of 4-fluoro-5-hydroxy-2-nitrobenzoic acid, and more preferably 30-50%.
In the invention, the volume ratio of the mass of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid to the volume of the methanol is preferably 1g (1-5) mL, and more preferably 1g (2-4) mL.
In the present invention, the mixing is preferably performed in the following manner: firstly, mixing 4-fluoro-5-hydroxy-2-nitrobenzoic acid with methanol, and then adding a molecular sieve catalyst. In the present invention, the esterification reaction is preferably carried out under stirring. In the invention, the temperature of the esterification reaction is preferably 60-90 ℃, and more preferably 70-85 ℃; the time is preferably 10 to 24 hours, and more preferably 12 to 20 hours.
In the present invention, after the esterification reaction, the esterification reaction liquid obtained is preferably quenched in the present invention. In the present invention, the quenching is preferably carried out by adding ice water. In the present invention, the volume ratio of the ice water to the esterification reaction liquid is preferably 1: 1.
The present invention also preferably comprises post-treating the obtained esterification reaction liquid, wherein the post-treatment comprises the following steps:
and carrying out solid-liquid separation on the esterification reaction liquid, and sequentially carrying out organic extraction, drying, extractant removal and recrystallization on the obtained liquid to obtain a pure 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester product.
In the present invention, the solid-liquid separation is preferably performed by filtration. The present invention does not require any particular filtration means, and filtration means known to those skilled in the art may be used.
In the present invention, it is preferable to recover and reuse the catalyst obtained after the solid-liquid separation. In the invention, the catalyst is preferably recovered by adopting a calcination mode, the calcination temperature is preferably 300-400 ℃, and the calcination time is preferably 1-2 h.
In the present invention, the extractant used in the organic extraction is preferably ethyl acetate. In the present invention, the volume ratio of the extractant to the liquid obtained after solid-liquid separation is preferably 1: 1. The invention extracts the target product 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester into an extractant phase by extraction.
In the invention, the drying agent used for drying is preferably one or more of anhydrous sodium sulfate, solid calcium oxide, anhydrous calcium chloride, anhydrous potassium carbonate and anhydrous magnesium sulfate; the mass ratio of the drying agent to the extraction phase is preferably 0.5: 1.
In the present invention, the solvent is preferably removed by rotary evaporation. In the invention, the temperature of the rotary evaporation is preferably 35-45 ℃, and more preferably 40 ℃. The invention has no special requirement on the time of the rotary evaporation so as to remove the extractant cleanly.
In the invention, the solvent used for recrystallization is preferably a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is preferably 1:2, the solid-liquid ratio of the solid product obtained after rotary evaporation to the mixed solvent is 1:1, and the invention has no special requirements on the specific implementation process of recrystallization.
In the invention, the synthetic route of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester is shown as a formula A:
the following examples are provided to illustrate the preparation of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate in detail, but they should not be construed as limiting the scope of the invention.
Example 1
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
10g of 4, 5-difluoro-2-nitrobenzoic acid and 13mL of water were added to the reaction vessel to form a suspension, and 20mL of a 30% aqueous NaOH solution was added dropwise. After the dropwise addition, the mixture was heated to 80 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 1 by hydrochloric acid, extracting by using 25mL ethyl acetate, and adding 20g of anhydrous sodium sulfate to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 35 ℃ to remove the extractant, thus obtaining a crude product. With 25mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 95% and the purity by HPLC was 99%.
Method for preparing 4-fluoro-5-hydroxy-2-nitrobenzoic acid1The H-NMR chart is shown in FIG. 1.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
Dissolving 8.5g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid in 15mL of methanol, stirring in an ice bath, adding 4g of 4A molecular sieve, heating the reaction solution to 70 ℃ and refluxing for 12h, and monitoring the reaction progress by TCL. After the reaction, 20mL of ice water was added, the mixture was stirred for 10min, and the molecular sieve was removed by filtration. Calcining the molecular sieve at 300 ℃ for 1h, and recovering; extracting the filtrate with 35mL of ethyl acetate, adding 10g of anhydrous sodium sulfate dry solution after extraction, performing rotary evaporation at 35 ℃, and removing the extractant to obtain a crude product. Recrystallization was carried out using 20mL of a mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 90% and the purity by HPLC 98.6%.
Process for preparing methyl 4-fluoro-5-hydroxy-2-nitrobenzoate1The H-NMR chart is shown in FIG. 2.
Example 2
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
20g of 4, 5-difluoro-2-nitrobenzoic acid and 30mL of methanol were added to the reaction vessel and mixed, and 40mL of 20% KOH aqueous solution was added dropwise. After the dropwise addition, the reaction mixture was heated to 85 ℃ for 20min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 3 by hydrochloric acid, extracting by using 70mL ethyl acetate, and adding 40g of anhydrous magnesium sulfate to dry an organic phase after the extraction is finished; rotary evaporation was carried out at 37 ℃ to remove the extractant and obtain the crude product. With 30mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 93% and the purity by HPLC 98.6%.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
Dissolving 15g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid in 30mL of methanol, stirring in an ice bath, adding 10g of a 3A molecular sieve, heating the reaction solution to 75 ℃, refluxing for 15h, and monitoring the reaction progress by TCL. After the reaction, 40mL of ice water was added, the mixture was stirred for 15min, and the molecular sieve was removed by filtration. Calcining the molecular sieve at 350 ℃ for 1h, and recovering; the filtrate was extracted with 50mL of ethyl acetate, and after completion of the extraction, 20g of dry anhydrous magnesium sulfate solution was added, and rotary evaporation was carried out at 37 ℃ to remove the extractant, thereby obtaining a crude product. The mixture of ethyl acetate and petroleum ether (1:2) 30mL is used for recrystallization to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 87.9% and the purity by HPLC was 98.9%.
Example 3
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
5g of 4, 5-difluoro-2-nitrobenzoic acid and 10mL of ethanol are added into the reaction kettle, mixed and dropwise added with 10mL of 40% NaOH aqueous solution. After the dropwise addition, the mixture was heated to 90 ℃ to react for 35min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 2 by hydrochloric acid, extracting by using 15mL of ethyl acetate, and adding 10g of anhydrous calcium chloride to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 40 ℃, and the extractant is removed, thus obtaining a crude product. With 10mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 91.4% and the purity by HPLC was 98.1%.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
4g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid is dissolved in 8mL of methanol, stirred in an ice bath, 1g of 5A molecular sieve is added, the reaction solution is heated to 85 ℃ and refluxed for 18h, and the reaction progress is monitored by TCL. After the reaction, 10mL of ice water was added, the mixture was stirred for 20min, and the molecular sieve was removed by filtration. Calcining the molecular sieve at 380 ℃ for 1.5h, and recovering; extracting the filtrate with 15mL of ethyl acetate, adding 8g of anhydrous calcium chloride dry solution after extraction, performing rotary evaporation at 35 ℃, and removing the extractant to obtain a crude product. Recrystallization was carried out using 10mL of a mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 87.5% and the purity by HPLC was 98.5%.
Example 4
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
40g of 4, 5-difluoro-2-nitrobenzoic acid and 60mL of acetone are added to the reaction vessel and mixed, and 80mL of 30% KOH aqueous solution are added dropwise. After the dropwise addition, the mixture was heated to 90 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 1 by hydrochloric acid, extracting by using 140mL of ethyl acetate, and adding 80g of anhydrous calcium oxide dry organic phase after the extraction is finished; rotary evaporation was carried out at 38 ℃ to remove the extractant and obtain the crude product. With 60mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 91.8% and the purity by HPLC was 98.5%.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
Dissolving 20g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid in 40mL of methanol, stirring in an ice bath, adding 15g of NKF-5-80W molecular sieve, heating the reaction solution to 80 ℃, refluxing for 18h, and monitoring the reaction progress by TCL. After the reaction, 40mL of ice water was added, the mixture was stirred for 15min, and the molecular sieve was removed by filtration. Calcining the molecular sieve at 400 ℃ for 2h, and recovering; and extracting the filtrate with 80mL of ethyl acetate, adding 30g of anhydrous calcium oxide dry solution after extraction is finished, performing rotary evaporation at 40 ℃, and removing an extracting agent to obtain a crude product. Recrystallizing with 40mL mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 89.9% and the purity by HPLC was 99.1%.
Example 5
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
100g of 4, 5-difluoro-2-nitrobenzoic acid and 130mL of chloroform were added to the reaction vessel, and 200mL of a 30% aqueous solution of lithium hydroxide was added dropwise. After the dropwise addition, the mixture was heated to 90 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 2 by hydrochloric acid, extracting by using 250mL of ethyl acetate, and adding 200g of anhydrous potassium carbonate to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 35 ℃ to remove the extractant, thus obtaining a crude product. With 250mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 92.4% and the purity by HPLC 98.5%.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
Dissolving 85g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid in 150mL of methanol, stirring in an ice bath, adding 40g of NKF-6-25 molecular sieve, heating the reaction liquid to 80 ℃, refluxing for 24h, and monitoring the reaction progress by TCL. After the reaction is finished, 200mL of ice water is added, the mixture is stirred for 30min, and the molecular sieve is removed by filtration. Calcining the molecular sieve at 400 ℃ for 2h, and recovering; the filtrate was extracted with 350mL ethyl acetate, and after extraction, 100g of dry anhydrous sodium sulfate solution was added, and rotary evaporation was carried out at 40 ℃ to remove the extractant, to obtain a crude product. Recrystallizing with 200mL mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 87.6% and the purity by HPLC was 98.2%.
Example 6
(1) Synthesis of 4-fluoro-5-hydroxy-2-nitrobenzoic acid
50g of 4, 5-difluoro-2-nitrobenzoic acid and 70mL of water were added to the reaction vessel to form a suspension, and 100mL of a 40% aqueous NaOH solution was added dropwise. After the dropwise addition, the mixture was heated to 80 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 3 by hydrochloric acid, extracting by using 130mL of ethyl acetate, and adding 100g of anhydrous sodium sulfate to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 35 ℃ to remove the extractant, thus obtaining a crude product. With 130mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 91% and the purity by HPLC 98%.
(2) Synthesis of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate
Dissolving 45g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid in 80mL of methanol, stirring in an ice bath, adding 20g of NKF-7SC molecular sieve, heating the reaction solution to 80 ℃, refluxing for 12h, and monitoring the reaction progress by TCL. After the reaction, 100mL of ice water was added and stirred for 10min, and the molecular sieve was removed by filtration. Calcining the molecular sieve at 300 ℃ for 1h, and recovering; the filtrate was extracted with 180mL ethyl acetate, after extraction, 50g of dry anhydrous sodium sulfate solution was added, rotary evaporation was carried out at 35 ℃ to remove the extractant, and the crude product was obtained. Recrystallization was carried out using 100mL of a mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 88.6% and the purity by HPLC 98.7%.
Comparative example 1
(1) 10g of 4, 5-difluoro-2-nitrobenzoic acid and 13mL of water were added to the reaction vessel to form a suspension, and 20mL of a 30% aqueous NaOH solution was added dropwise. After the dropwise addition, the mixture was heated to 80 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, adjusting the pH value to 5 by hydrochloric acid, extracting by using 25mL ethyl acetate, and adding 20g of anhydrous sodium sulfate to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 35 ℃ to remove the extractant, thus obtaining a crude product. With 25mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 64.6% and the purity by HPLC was 87.9%.
(2) Same as in step (2) of example 1.
Comparative example 2
(1) 10g of 4, 5-difluoro-2-nitrobenzoic acid and 13mL of water were added to the reaction vessel to form a suspension, and 20mL of a 30% aqueous NaOH solution was added dropwise. After the dropwise addition, the mixture was heated to 80 ℃ to react for 30min, and the reaction progress was monitored by TCL. After the reaction is finished, cooling to room temperature, extracting with 25mL ethyl acetate, and adding 20g anhydrous sodium sulfate to dry an organic phase after the extraction is finished; rotary evaporation is carried out at 35 ℃ to remove the extractant, thus obtaining a crude product. With 25mL of toluene: and recrystallizing the mixed solution of cyclohexane (1:1) to obtain the 4-fluoro-5-hydroxy-2-nitrobenzoic acid. The yield was 24.6% and the purity by HPLC was 57.9%.
(2) Same as in step (2) of example 1.
As can be seen from comparative examples 1 and 2, in the substitution reaction of the present invention, the pH of the solution needs to be adjusted to 1-3, and the yield and purity of the product can be higher. Because the pH is adjusted to be acidic, by-products and impurities in the reaction liquid exist in the water phase, and the organic phase is a product, so that the product purity is high.
Comparative example 3
(1) Same as in step (1) of example 1.
(2) 8.5g of 4-fluoro-5-hydroxy-2-nitrobenzoic acid was dissolved in 15mL of methanol, stirred in ice bath, the reaction was heated to 70 ℃ and refluxed for 12h, and the progress of the reaction was monitored by TCL. And after the reaction is finished, adding 20mL of ice water, stirring for 10min, extracting the solution with 35mL of ethyl acetate, adding 10g of anhydrous sodium sulfate dry solution after the extraction is finished, performing rotary evaporation at 35 ℃, and removing the extractant to obtain a crude product. Recrystallization was carried out using 20mL of a mixed solution of ethyl acetate and petroleum ether (1:2) to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester. The yield was 46% and the purity by HPLC was 67%.
As can be seen from comparative example 3, the catalyst plays an important role in the esterification reaction. Because the esterification reaction of the invention is reversible and the reaction is very slow, the reaction process can be accelerated after the catalyst is added, so that the reaction is more thorough. The method adopts the molecular sieve as the catalyst, not only has good catalytic effect, but also can recycle the catalyst, thereby reducing the pollution to the environment.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of methyl 4-fluoro-5-hydroxy-2-nitrobenzoate comprises the following steps:
(1) mixing 4, 5-difluoro-2-nitrobenzoic acid, inorganic strong base and a polar solvent for substitution reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid;
(2) mixing the 4-fluoro-5-hydroxy-2-nitrobenzoic acid, methanol and a molecular sieve catalyst, and carrying out esterification reaction to obtain 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester.
2. The preparation method according to claim 1, wherein the inorganic strong base is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and rubidium hydroxide.
3. The preparation method according to claim 1 or 2, wherein the molar ratio of the 4, 5-difluoro-2-nitrobenzoic acid to the strong inorganic base is 1 (2-5).
4. The method according to claim 1, wherein the temperature of the substitution reaction is 60 to 100 ℃ and the time is 20 to 60 min.
5. The method according to claim 1, wherein the polar solvent is one or more selected from methanol, ethanol, diethyl ether, chloroform and acetone.
6. The method according to claim 1, wherein the molecular sieve catalyst is one or more of a 3A molecular sieve, a 4A molecular sieve, a 5A molecular sieve, an NKF-5-80W molecular sieve, an NKF-6-25 molecular sieve and an NKF-7SC molecular sieve.
7. The preparation method according to claim 1 or 6, wherein the mass of the molecular sieve catalyst is 20-80% of the mass of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid.
8. The preparation method according to claim 1, wherein the volume ratio of the mass of the 4-fluoro-5-hydroxy-2-nitrobenzoic acid to the volume of the methanol is 1g (1-5) mL.
9. The preparation method according to claim 1, wherein the esterification reaction is carried out at a temperature of 60 to 90 ℃ for 10 to 24 hours.
10. The method according to claim 1, further comprising, after the esterification reaction, post-treating the obtained esterification reaction liquid, wherein the post-treating comprises the steps of:
and carrying out solid-liquid separation on the esterification reaction liquid, and sequentially carrying out organic extraction, drying, extractant removal and recrystallization on the obtained liquid to obtain a pure 4-fluoro-5-hydroxy-2-nitrobenzoic acid methyl ester product.
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| CN102633639A (en) * | 2012-04-06 | 2012-08-15 | 华远医药研究院有限公司 | Synthesis process for trifluoroacetic acid ethyl ester |
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