CN115028522A - Preparation method of 2, 7-dihydroxy-9-fluorenone - Google Patents

Preparation method of 2, 7-dihydroxy-9-fluorenone Download PDF

Info

Publication number
CN115028522A
CN115028522A CN202210897816.3A CN202210897816A CN115028522A CN 115028522 A CN115028522 A CN 115028522A CN 202210897816 A CN202210897816 A CN 202210897816A CN 115028522 A CN115028522 A CN 115028522A
Authority
CN
China
Prior art keywords
fluorene
dihydroxy
diacyl
dibenzoate
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210897816.3A
Other languages
Chinese (zh)
Other versions
CN115028522B (en
Inventor
郝卫
陈一贤
彭慧珍
冯冬祥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Lupu Biotechnology Co ltd
Original Assignee
Hangzhou Lupu Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Lupu Biotechnology Co ltd filed Critical Hangzhou Lupu Biotechnology Co ltd
Priority to CN202210897816.3A priority Critical patent/CN115028522B/en
Publication of CN115028522A publication Critical patent/CN115028522A/en
Application granted granted Critical
Publication of CN115028522B publication Critical patent/CN115028522B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/04—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides onto unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a preparation method of 2, 7-dihydroxy-9-fluorenone, which comprises the following steps: (1) mixing benzoic acid, an oxidant A, fluorene, a solvent A and a catalyst A for reaction to obtain 9H-fluorene-2, 7-diacyl dibenzoate; (2) carrying out oxidation reaction on 9H-fluorene-2, 7-diacyl dibenzoate, a solvent B, a catalyst B and an oxidant B to obtain 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate; (3) mixing 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate with a solvent C and alkali for hydrolysis reaction to obtain 2, 7-dihydroxy-9-fluorenone; the purity of the product is more than 99.5 percent, and the yield is more than 92 percent. The method has the advantages of good atomic economy, environmental protection, simple preparation process, short synthetic route, high product purity, high yield and the like.

Description

Preparation method of 2, 7-dihydroxy-9-fluorenone
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicine intermediates, and particularly relates to a preparation method of 2, 7-dihydroxy-9-fluorenone.
Background
2, 7-dihydroxy-9-fluorenone is an important organic synthetic raw material and can be used for preparing a fluorescent organic silicon polymer material; can also be used for preparing thermoplastic resin of fluorenyl polyether sulfone ketone; in addition, the derivative can be used as tylolone (bis-diethylamino-9-fluorenone) for synthesizing virus interferon and a key intermediate of 2-hydroxyaminoacetyl-9-fluorenone for resisting spasm. Therefore, the synthesis of the 2, 7-dihydroxy-9-fluorenone has important research value.
The synthesis of 2, 7-dihydroxy-9-fluorenone was first reported by Krishna in 1967 (Journal of Medicinal Chemistry,1967,10: 99-101). Fluorene is used as a raw material, and 2, 7-dihydroxy-9-fluorenone is obtained through sulfonation, oxidation, alkali fusion and ring-closure reaction. The method has the advantages of easily available raw materials and low cost. However, potassium permanganate is selected as an oxidant in the preparation process, so that a large amount of manganese dioxide solid waste is generated, the treatment is difficult, the last two steps of the reaction are high-temperature solid-phase reaction, the operation mode and the mass transfer process in the reaction process are difficult, the requirement on reaction equipment is high during production, and the reaction progress degree is difficult to control. The synthetic route is as follows:
Figure BDA0003769745140000011
in 1973, Horner et al (Justus Liebigs Annalen der Chemie,1973,6(5): 910-935) reported that methyl 2-bromo-5-methoxybenzoate and p-iodoanisole were used as raw materials to produce 4,4 '-diethyidiphenyl-2-carboxylic acid and 4, 4' -diethyidiphenyl-carboxylic acid under the catalysis of copper powder. The 4, 4' -dimethyl ether biphenyl-2-formic acid is closed by ring under the action of polyphosphate, and then the methoxyl is converted into hydroxyl by hydrobromic acid to obtain a target product. The method has mild conditions, but the raw materials are high in price, and the self-coupling product is generated in the first step, so that the yield is low. The synthetic route is as follows:
Figure BDA0003769745140000021
in 1976 Burke et al (Synthetic Communications,1976,6: 371-. The method uses SnCl 2 The nitro is reduced, and the cost is high. The synthetic route is as follows:
Figure BDA0003769745140000022
in 2004, Epperson et al (Bioorganic)&media chemistry,2004,12 (17): 4601-4611.) reported methyl 2-bromo-5-hydroxybenzoate and 4-hydroxyphenylboronic acid in Pd 2 dba 3 Carrying out Suzuki coupling reaction under catalysis to obtain 4, 4' -dihydroxy biphenyl-2-methyl formate, and then carrying out ring closure to obtain a target product. The reaction uses homogeneous Pd catalyst, and is expensive, and the starting material is expensive, so that the method is not suitable for industrial production. The synthetic route is as follows:
Figure BDA0003769745140000023
in 2008 Jeffrey et al (Journal of Materials Chemistry,2008,18(28):3361-3365.) report fluorenones as starting Materials, acetic anhydride as acylating agent, via anhydrous AlCl 3 Carrying out a Friedel-crafts acylation reaction under the catalysis of (1), carrying out Baeyer-Villiger oxidation rearrangement reaction on a product by m-chloroperoxybenzoic acid (m-CPBA) and trifluoroacetic acid in a chloroform solvent, oxidizing the product by sodium dichromate, and finally hydrolyzing to obtain a target product. The method has higher cost, needs to pay attention to safety when using peroxide for production, and is difficult to carry out post-treatment on sodium dichromate. The synthetic route is as follows:
Figure BDA0003769745140000031
the prior art mainly has the following problems: 1) due to the defects of high cost, dangerous operation, complexity, large solvent consumption and the like, satisfactory results are difficult to obtain in industrial preparation; 2) the route has the advantages of high raw material cost, low yield and difficult product purification, and particularly, when potassium permanganate is selected as an oxidant for reaction in the preparation process of 2, 7-dipotassium sulfonate-9-fluorenone, a large amount of manganese dioxide solid waste is generated and is difficult to treat; 3) the last two steps of the reaction are high-temperature solid-phase reactions, the operation mode and the mass transfer process in the reaction process are difficult, the requirements on reaction equipment are high during production, and the reaction progress degree is difficult to control.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention provides a preparation method of 2, 7-dihydroxy-9-fluorenone. The invention constructs 9H-fluorene-2, 7-diacyl dibenzoate by a C-H activation method and obtains 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate by catalytic oxidation, and the preparation method has simple preparation process and short synthetic route.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of 2, 7-dihydroxy-9-fluorenone comprises the following steps:
(1) mixing benzoic acid, an oxidant A, fluorene, a solvent A and a catalyst A for reaction to obtain 9H-fluorene-2, 7-diacyl dibenzoate;
(2) carrying out oxidation reaction on 9H-fluorene-2, 7-diacyl dibenzoate, a solvent B, a catalyst B and an oxidant B to obtain 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate; (3) mixing 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate with a solvent C and alkali for hydrolysis reaction to obtain 2, 7-dihydroxy-9-fluorenone; the purity of the product is more than 99.5 percent, and the yield is more than 92 percent.
In the process of preparing 9H-fluorene-2, 7-diacyl dibenzoate, the invention adopts a C-H activation method and a metal catalysis method, avoids using a sulfonated alkali fusion method, can be carried out without high temperature, and has benzoyl groups on two positions of 2 and 7.
In the process of preparing 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate, the invention adopts a catalytic oxidation method, the mass transfer process is better in homogeneous phase, the reaction selectivity is high, and the product can be obtained by cooling, separating and filtering and rinsing with water after the reaction is finished.
In the process of preparing 2, 7-dihydroxy-9-fluorenone, the invention is hydrolyzed in catalytic amount of alkali, and 2, 7-dihydroxy-9-fluorenone can be directly obtained by adjusting acid after hydrolysis. The purity of the 2, 7-dihydroxy-9-fluorenone prepared by the method is more than 99.5 percent, and the yield is more than 92 percent.
Preferably, in the step (1), the oxidant A is one or any combination of more than two of sodium persulfate, potassium peroxymonosulfonate, silver oxide, iodobenzene diacetate and iodosobenzene; the solvent A is one or the combination of more than two of dichloroethane, chloroform, DMF, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the catalyst A is one or the combination of more than two of copper iodide, copper chloride, copper acetate, palladium chloride, palladium acetate, palladium nitrate and palladium bromide.
Preferably, the reaction temperature in the step (1) is 100-140 ℃ and the time is 5-30 h.
Preferably, in the step (1), the molar ratio of fluorene, benzoic acid, oxidant a and catalyst a is 1: 2-3: 2-3: 0.01 to 0.05; the mass ratio of the solvent A to the fluorene is 5-10: 1.
preferably, in the step (2), the oxidant B is one or any combination of more than two of tert-butyl hydroperoxide, hydrogen peroxide, oxygen and peroxyacetic acid; the solvent B is one or the combination of more than two of dichloroethane, chloroform, DMF, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the catalyst B is one or the combination of more than two of cuprous chloride, copper iodide, copper sulfate, copper acetate, potassium iodide and iodine.
Preferably, the reaction temperature of the step (2) is 20-80 ℃, and the time is 2-12 h.
Preferably, in the step (2), the mass ratio of the solvent B to the 9H-fluorene-2, 7-diacyl dibenzoate is 5-10: 1, the molar ratio of the oxidant B to the 9H-fluorene-2, 7-diacyl dibenzoate is 1-5: 1, the mass ratio of the catalyst B to the oxidant B is 0.05-0.3: 1.
preferably, in the step (3), the solvent C is one or any combination of more than two of ethanol, methanol, water, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the alkali is one or more of sodium hydroxide, potassium carbonate, sodium bicarbonate and sodium hydrogen.
Preferably, the reaction temperature of the step (3) is 80-100 ℃, and the reaction time is 5-10 h.
Preferably, in the step (3), the mass ratio of the solvent C to the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is 5-10: 1, the molar ratio of the base to 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is 1-3: 1.
the reaction process of the invention is as follows:
Figure BDA0003769745140000051
compared with the prior art, the invention has the beneficial effects that:
1. high-temperature solid-phase reaction is avoided, so that the operation mode and the mass transfer process in the reaction process are easier, and industrialization is easier;
2. the method avoids the byproducts which are difficult to remove, greatly improves the yield, improves the yield by more than 10 percent compared with the traditional process, and obviously improves the product purity;
3. a large amount of solid waste is avoided, the environment is protected, and green chemistry is realized;
4. the 9H-fluorene-2, 7-diacyl dibenzoate is prepared by a C-H activation method, and the atom economy is good.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of 2, 7-dihydroxy-9-fluorenone.
Detailed Description
The technical solutions of the present invention are further specifically described below by examples, which are for illustration of the present invention and are not intended to limit the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Example 1
A preparation method of 2, 7-dihydroxy-9-fluorenone comprises the following steps:
(1) preparation of 9H-fluorene-2, 7-diacyldibenzoate:
mixing benzoic acid, an oxidant A, fluorene, a solvent A and a catalyst A for reaction to obtain 9H-fluorene-2, 7-diacyl dibenzoate;
in the invention, the raw materials are all conventional commercial products in the field or are prepared by conventional technical means in the field if no special indication is provided.
In the invention, the catalyst A comprises one or more of copper iodide, copper chloride, copper acetate, palladium chloride, palladium acetate, palladium nitrate and palladium bromide. In the present invention, the solvent a is preferably toluene or xylene. In the present invention, the molar ratio of fluorene to benzoic acid is preferably 1: 2 to 3, and more preferably 1: 2.15. in the present invention, the molar ratio of fluorene to iodosobenzene is preferably 1: 2-3, more preferably 1: 2.1. in the invention, the mass ratio of the solvent A toluene to the fluorene is preferably 5-10: 1, more preferably 7: 1. in the invention, the molar ratio of the palladium acetate to the fluorene of the catalyst A is preferably 0.01-0.05: 1, more preferably 0.03: 1.
in the invention, the condensation reaction temperature is preferably 100-140 ℃, and more preferably 110-130 ℃; the time of the condensation reaction is preferably 5 to 30 hours, and more preferably 10 to 15 hours. In the present invention, it is preferable to carry out the condensation reaction while distilling off the moisture generated by the condensation reaction.
After the condensation reaction, the invention preferably carries out reduced pressure distillation, cooling, filtration and refining on the obtained condensation reaction product in sequence to obtain the 9H-fluorene-2, 7-diacyl dibenzoate.
In the invention, the temperature of the reduced pressure distillation is preferably 70-90 ℃. In the present invention, the cooling method is preferably ice water cooling. The refining mode is preferably that the hydrolysate is put into methanol solution for heating and stirring washing. In the invention, the mass ratio of the methanol to the wet weight of the hydrolysate is preferably 0.5-3: 1, more preferably 1.0 to 1.5: 1. the refining temperature is preferably 40-50 ℃; the refining time is preferably 1-2 h. The specific operation of the agitation washing is not particularly limited in the present invention, and a refining method known to those skilled in the art may be used. The target product 9H-fluorene-2, 7-diacyl dibenzoate is prepared by the method.
(2) Preparation of 9-oxo-9H-fluorene-2, 7-diacyldibenzoate:
the condensation reaction product is directly mixed with an oxidant B, a solvent B and a catalyst B for oxidation reaction to obtain the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate.
The condensation reaction product is directly mixed with a solvent B and a catalyst B, and then an oxidant B is dripped to carry out oxidation reaction. In the invention, the dripping speed is preferably 4-5 mL/min. In the invention, the oxidant comprises one or more of hydrogen peroxide, tert-butyl peroxide, peracetic acid and oxygen. In the invention, the solvent B is preferably one or more of dichloroethane, chloroform, DMF, acetonitrile, dioxane, DMSO, toluene and chlorobenzene. In the invention, the catalyst B comprises one or more of cuprous chloride, ketone iodide, copper sulfate, copper acetate, potassium iodide and iodine. In the invention, the mass ratio of the dichloroethane as the solvent B to the 9H-fluorene-2, 7-diacyl dibenzoate is preferably 5-10: 1, more preferably 6 to 7: 1. in the invention, the molar ratio of the tert-butyl peroxide to the 9H-fluorene-2, 7-diacyl dibenzoate is preferably 1-5: 1, more preferably 2.7: 1. in the invention, the mass ratio of the copper acetate to the tert-butyl peroxide is preferably 0.05-0.3: 1, more preferably 0.1: 1.
in the invention, the temperature of the oxidation reaction is preferably 20-80 ℃, and further preferably 65-70 ℃; the reaction time is preferably 2 to 12 hours, and more preferably 5 to 7 hours.
After the oxidation reaction, the obtained oxidation reaction product is sequentially cooled, filtered and refined to obtain the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate.
In the present invention, the cooling method is preferably normal temperature water cooling. In the present invention, the purification method is preferably to wash the oxidation product by adding it to an aqueous solution of sodium dithionite. In the invention, the mass ratio of the sodium hydrosulfite to the wet weight of the oxidation product is preferably 0.1-1: 1, more preferably 0.2 to 0.3: 1. in the invention, the mass ratio of the stirred and washed water to the wet weight of the oxidation product is preferably 0.5-5: 1, and more preferably 1.5: 1; the preferred temperature of the stirring and washing is 20-40 ℃; the recrystallization time is preferably 1-2 h. The specific operation of the agitation washing is not particularly limited in the present invention, and a refining method known to those skilled in the art may be used. The key intermediate 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is prepared by catalytic oxidation.
(3) Preparation of 2, 7-dihydroxy-9-fluorenone:
under the protection of nitrogen, mixing the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate, a solvent C and alkali for hydrolysis reaction, and adjusting acid to obtain 2, 7-dihydroxy-9-fluorenone after the reaction is finished;
in the present invention, the solvent includes one or more of ethanol, methanol, water, acetonitrile, dioxane, DMSO, toluene, chlorobenzene. In the present invention, the base is preferably one or more of sodium hydroxide, potassium carbonate, sodium bicarbonate, sodium hydrogen. In the invention, the mass ratio of the solvent water to the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is preferably 5-10: 1, and more preferably 6 to 7: 1. in the invention, the molar ratio of the alkali sodium hydroxide to the 9H-fluorene-2, 7-diacyl dibenzoate is preferably 1-3: 1, more preferably 2.0: 1.
after the hydrolysis reaction, the obtained hydrolysis reaction product is sequentially cooled, acid-regulated, filtered and refined to obtain the 2, 7-dihydroxy-9-fluorenone.
In the present invention, the cooling method is preferably normal temperature water cooling. In the invention, the acid adjustment is carried out by using hydrochloric acid, and the molar ratio of the hydrochloric acid to sodium hydroxide is preferably 1.5-3: 1, more preferably 2.1: 1. the purification is preferably carried out by washing the hydrolysate with methanol solution. In the invention, the mass ratio of the methanol to the wet weight of the hydrolysate is preferably 0.5-3: 1, more preferably 1.0 to 1.5: 1. the refining temperature is preferably 10-20 ℃; the refining time is preferably 1-2 h. The specific operation of the agitation washing is not particularly limited in the present invention, and a refining method known to those skilled in the art may be used. The target product 2, 7-dihydroxy-9-fluorenone is prepared by hydrolytic acidification.
Example 2
(1) Synthesis of Compound 1:
Figure BDA0003769745140000081
adding 50g of fluorene, 79g of benzoic acid, 124g of silver oxide, 2g of palladium acetate and 350g of toluene into a reaction vessel provided with a thermometer, a stirrer and a water separator, controlling the reaction temperature to be 115 ℃, distilling off water generated by the reaction while reacting, cooling to 70 ℃ after reacting for 10-15 hours, filtering while hot, concentrating an organic layer under reduced pressure until a large amount of solid is precipitated, adding 100g of methanol, heating to 50 ℃, stirring for 1 hour, cooling to 10 ℃, and performing suction filtration to obtain 9H-fluorene-2, 7-diacyl methyl dibenzoate, drying at 70 ℃ by 105.3g, and obtaining the yield of 85.4%.
(2) Synthesis of Compound 2:
Figure BDA0003769745140000082
100g of 9H-fluorene-2, 7-diacyl-dibenzoic acid methyl ester, 8.2g of copper acetate, 650g of dichloroethane were charged into a reactor equipped with a thermometer, a stirrer and a constant-pressure dropping device. The temperature was gradually raised to 50 ℃ and 118.6g of 70% t-butyl peroxide was gradually added dropwise. And after dripping, continuously preserving the heat for 10 hours. After the reaction is finished, the temperature is reduced to 10 ℃, and the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate wet product is obtained by pumping filtration, wherein the wet product is 115g, the wet product is stirred and washed by 20g of sodium hydrosulfite and 115g of water for 1 hour, the refined product of the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate is obtained by pumping filtration, the refined product is dried to obtain 96.8g, and the yield is 94.0%.
(3) Synthesis of Compound 3:
Figure BDA0003769745140000083
700g of water and 60g of sodium carbonate are added into a reaction vessel, and 100g of 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is added under the protection of nitrogen. Raising the temperature to 90 ℃ under the nitrogen atmosphere, and preserving the temperature for 7 h. And after the reaction is finished, cooling to 5 ℃, slowly dripping 47g of concentrated hydrochloric acid into the reaction solution, continuing to keep the temperature for 1h at 5 ℃ after dripping is finished, and performing suction filtration to obtain 52g of a wet product of the 2, 7-dihydroxy-9-fluorenone. And (3) washing the wet product with 52g of methanol at 15-20 ℃ for 1h, cooling to 5 ℃, performing suction filtration, drying and taking 47.1g of 2, 7-dihydroxy-9-fluorenone, wherein the HPLC purity is 99.8 percent, and the yield is 94.2 percent. The hydrogen spectrum of the resulting product is shown in figure 1, 1 H NMR(500MHz,d 6 -DMSO)δ9.83(s,2H),7.36(d,J＝8.0Hz,2H),6.92–6.82(m,4H).
example 3
(1) Synthesis of Compound 1:
Figure BDA0003769745140000091
adding 50g of fluorene, 79g of benzoic acid, 150g of sodium persulfate, 2g of palladium acetate and 350g of toluene into a reaction vessel provided with a thermometer, a stirrer and a water separator, controlling the reaction temperature to be 115 ℃, distilling off water generated by the reaction while carrying out the reaction, cooling to 70 ℃ after reacting for 10-15 hours, filtering while hot, concentrating an organic layer under reduced pressure until a large amount of solid is separated out, adding 100g of methanol, heating to 50 ℃, stirring for 1 hour, cooling to 10 ℃, and carrying out suction filtration to obtain 9H-fluorene-2, 7-diacyl dibenzoate, drying 103.1g at 70 ℃, wherein the yield is 84.2%.
(2) Synthesis of Compound 2:
Figure BDA0003769745140000092
100g of 9H-fluorene-2, 7-diacyldibenzoic acid methyl ester, 7.0g of copper sulfate and 650g of dichloroethane were charged into a reactor equipped with a thermometer, a stirrer and a constant-pressure dropping device. The temperature was slowly raised to 50 ℃ and 118.6g of 70% t-butyl peroxide was slowly added dropwise. And after dripping, keeping the temperature for 14 hours. After the reaction is finished, the temperature is reduced to 10 ℃, and the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate wet product is obtained by pumping filtration, wherein the wet product is 115g, the wet product is stirred and washed by 20g of sodium hydrosulfite and 115g of water for 1 hour, the refined product of the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate is obtained by pumping filtration, the refined product is dried to obtain 95.8g, and the yield is 93.0%.
(3) Synthesis of Compound 3:
Figure BDA0003769745140000093
700g of water and 19g of sodium hydroxide are added into a reaction vessel, and 100g of methyl 9-oxo-9H-fluorene-2, 7-diacyldibenzoate is added under the protection of nitrogen. Raising the temperature to 90 ℃ under the nitrogen atmosphere, and preserving the temperature for 7 h. And after the reaction is finished, cooling to 5 ℃, slowly dripping 47g of concentrated hydrochloric acid into the reaction solution, continuing to keep the temperature for 1h at 5 ℃ after dripping is finished, and performing suction filtration to obtain 52g of a wet product of the 2, 7-dihydroxy-9-fluorenone. And (3) washing the wet product with 52g of methanol at 15-20 ℃ for 1h, cooling to 5 ℃, performing suction filtration, drying and taking 46.5g of 2, 7-dihydroxy-9-fluorenone, wherein the HPLC purity is 99.6%, and the yield is 93%.
Example 4
(1) Synthesis of Compound 1:
Figure BDA0003769745140000101
adding 50g of fluorene, 79g of benzoic acid, 139g of iodosobenzene, 2g of palladium acetate and 350g of toluene into a reaction vessel provided with a thermometer, a stirrer and a water separator, controlling the reaction temperature to be 115 ℃, distilling off water generated by the reaction while reacting, cooling to 70 ℃ after reacting for 10-15 hours, filtering while hot, concentrating an organic layer under reduced pressure until a large amount of solid is separated out, adding 100g of methanol, heating to 50 ℃, stirring for 1 hour, cooling to 10 ℃, and performing suction filtration to obtain 9H-fluorene-2, 7-diacyl dibenzoate, drying 101.2g at 70 ℃ and obtaining the yield of 82.7%.
(2) Synthesis of Compound 2:
Figure BDA0003769745140000102
100g of 9H-fluorene-2, 7-diacyldibenzoic acid methyl ester, 3.0g of cupric chloride, 650g of dichloroethane were charged into a reactor equipped with a thermometer, a stirrer, and a constant-pressure dropping device. The temperature was slowly raised to 50 ℃ and 118.6g of 70% t-butyl peroxide was slowly added dropwise. And after dripping, keeping the temperature for 14 hours. After the reaction is finished, the temperature is reduced to 10 ℃, and the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate wet product is obtained by pumping filtration, wherein the wet product is 115g, the wet product is stirred and washed by 20g of sodium hydrosulfite and 115g of water for 1 hour, the refined product of the 9-oxo-9H-fluorene-2, 7-diacyl methyl dibenzoate is obtained by pumping filtration, the refined product is dried to obtain 95.7g, and the yield is 92.9%.
(3) Synthesis of Compound 3:
Figure BDA0003769745140000103
700g of water and 69g of potassium carbonate are added into a reaction vessel, and 100g of methyl 9-oxo-9H-fluorene-2, 7-diacyldibenzoate is added under the protection of nitrogen. Raising the temperature to 90 ℃ in the nitrogen atmosphere, and preserving the heat for 7 hours. And after the reaction is finished, cooling to 5 ℃, slowly dripping 47g of concentrated hydrochloric acid into the reaction solution, keeping the temperature for 1h at 5 ℃ after dripping is finished, and performing suction filtration to obtain 52g of a wet product of the 2, 7-dihydroxy-9-fluorenone. And (3) stirring and washing the wet product for 1h at 15-20 ℃ by using 52g of methanol, cooling to 5 ℃, performing suction filtration, drying and obtaining 46.3g of 2, 7-dihydroxy-9-fluorenone with the yield of 92.6%.
The method has the advantages of simple preparation process, short synthetic route, easy realization of industrialization and the like, and has the advantages of good atomic economy, environmental protection, high product purity, high yield and the like.
The present invention is described in detail with reference to the examples, but the description is only a specific embodiment of the present invention, and the present invention is not to be construed as being limited to the claims. It should be noted that, for those skilled in the art, variations and modifications made within the scope of the present invention shall fall within the scope of the claims of the present invention without departing from the spirit of the present invention.

Claims (10)

1. A preparation method of 2, 7-dihydroxy-9-fluorenone is characterized by comprising the following steps:
(1) mixing benzoic acid, an oxidant A, fluorene, a solvent A and a catalyst A for reaction to obtain 9H-fluorene-2, 7-diacyl dibenzoate;
(2) carrying out oxidation reaction on 9H-fluorene-2, 7-diacyl dibenzoate, a solvent B, a catalyst B and an oxidant B to obtain 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate;
(3) mixing 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate with a solvent C and alkali for hydrolysis reaction to obtain 2, 7-dihydroxy-9-fluorenone; the purity of the product is more than 99.5 percent, and the yield is more than 92 percent.
2. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 1, wherein: in the step (1), the oxidant A is one or any combination of more than two of sodium persulfate, potassium peroxymonosulfonate, silver oxide, iodobenzene diacetate and iodosobenzene; the solvent A is one or the combination of more than two of dichloroethane, chloroform, DMF, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the catalyst A is one or the combination of more than two of copper iodide, copper chloride, copper acetate, palladium chloride, palladium acetate, palladium nitrate and palladium bromide.
3. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 2, wherein: the reaction temperature of the step (1) is 100-140 ℃, and the reaction time is 5-30 h.
4. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 2, wherein: in the step (1), the molar ratio of fluorene, benzoic acid, oxidant A and catalyst A is 1: 2-3: 2-3: 0.01 to 0.05; the mass ratio of the solvent A to the fluorene is 5-10: 1.
5. the method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 1, wherein: in the step (2), the oxidant B is one or any combination of more than two of tert-butyl hydroperoxide, hydrogen peroxide, oxygen and peroxyacetic acid; the solvent B is one or the combination of more than two of dichloroethane, chloroform, DMF, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the catalyst B is one or the combination of more than two of cuprous chloride, copper iodide, copper sulfate, copper acetate, potassium iodide and iodine.
6. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 5, wherein: the reaction temperature of the step (2) is 20-80 ℃, and the reaction time is 2-12 h.
7. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 5, wherein: in the step (2), the mass ratio of the solvent B to the 9H-fluorene-2, 7-diacyl dibenzoate is 5-10: 1, the molar ratio of the oxidant B to the 9H-fluorene-2, 7-diacyl dibenzoate is 1-5: 1, the mass ratio of the catalyst B to the oxidant B is 0.05-0.3: 1.
8. the method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 1, wherein: in the step (3), the solvent C is one or any combination of more than two of ethanol, methanol, water, acetonitrile, dioxane, DMSO, toluene and chlorobenzene; the alkali is one or more of sodium hydroxide, potassium carbonate, sodium bicarbonate and sodium hydrogen.
9. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 8, wherein: the reaction-temperature of the step (3) is 80-100 ℃, and the time is 5-10 h.
10. The method for preparing 2, 7-dihydroxy-9-fluorenone according to claim 8, wherein: in the step (3), the mass ratio of the solvent C to the 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is 5-10: 1, the molar ratio of the alkali to 9-oxo-9H-fluorene-2, 7-diacyl dibenzoate is 1-3: 1.
CN202210897816.3A 2022-07-28 2022-07-28 Preparation method of 2, 7-dihydroxy-9-fluorenone Active CN115028522B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210897816.3A CN115028522B (en) 2022-07-28 2022-07-28 Preparation method of 2, 7-dihydroxy-9-fluorenone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210897816.3A CN115028522B (en) 2022-07-28 2022-07-28 Preparation method of 2, 7-dihydroxy-9-fluorenone

Publications (2)

Publication Number Publication Date
CN115028522A true CN115028522A (en) 2022-09-09
CN115028522B CN115028522B (en) 2023-10-24

Family

ID=83130294

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210897816.3A Active CN115028522B (en) 2022-07-28 2022-07-28 Preparation method of 2, 7-dihydroxy-9-fluorenone

Country Status (1)

Country Link
CN (1) CN115028522B (en)

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4618704A (en) * 1978-05-05 1986-10-21 Basf Aktiengesellschaft Acyloxy-2-butenes and their preparation
US5942641A (en) * 1993-06-18 1999-08-24 Otsuka Pharmaceutical Co., Ltd. Fluorenone derivatives, process for preparing the same and central or peripheral nerve degeneration repair and protective agent
EP0978503A1 (en) * 1998-08-05 2000-02-09 Clariant GmbH Synthesis of t-butyl o-(p-tolyl)benzoate by reaction of o-(p-tolyl)benzoic acid with isobutene using acid catalysis
JP2002332262A (en) * 2001-05-08 2002-11-22 Chisso Corp Fluorene derivative, antiferroelectric liquid crystal composition containing the same and liquid crystal display element produced by using the composition
CN1754867A (en) * 2004-09-28 2006-04-05 上海焦化有限公司 Method for oxidizing fluorene to 9-fluorenone
US20100286440A1 (en) * 2009-05-07 2010-11-11 Celanese International Corporation Vinyl Ester production from Acetylene and Carboxylic Acid utilizing homogeneous catalyst
CN102424651A (en) * 2011-11-02 2012-04-25 台州明翔化工有限公司 Preparation method of 2,7-diacetoxy-9-fluorenone and 2,7-dyhydroxyl-9-fluorenone
CN103204781A (en) * 2013-03-14 2013-07-17 武汉大学 2, 7-bi-substituted fluorenone derivative and preparation method and application thereof
CN105330522A (en) * 2015-10-26 2016-02-17 江西师范大学 Preparation method of benzo [ b ] fluorenone series compounds
CN110194745A (en) * 2018-02-26 2019-09-03 云南大学 Fluorenes ketone compounds, preparation method and the usage
CN113173854A (en) * 2021-04-23 2021-07-27 中国科学院上海有机化学研究所 Preparation method of chiral beta-acyloxy carboxylic ester compound

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4618704A (en) * 1978-05-05 1986-10-21 Basf Aktiengesellschaft Acyloxy-2-butenes and their preparation
US5942641A (en) * 1993-06-18 1999-08-24 Otsuka Pharmaceutical Co., Ltd. Fluorenone derivatives, process for preparing the same and central or peripheral nerve degeneration repair and protective agent
EP0978503A1 (en) * 1998-08-05 2000-02-09 Clariant GmbH Synthesis of t-butyl o-(p-tolyl)benzoate by reaction of o-(p-tolyl)benzoic acid with isobutene using acid catalysis
JP2002332262A (en) * 2001-05-08 2002-11-22 Chisso Corp Fluorene derivative, antiferroelectric liquid crystal composition containing the same and liquid crystal display element produced by using the composition
CN1754867A (en) * 2004-09-28 2006-04-05 上海焦化有限公司 Method for oxidizing fluorene to 9-fluorenone
US20100286440A1 (en) * 2009-05-07 2010-11-11 Celanese International Corporation Vinyl Ester production from Acetylene and Carboxylic Acid utilizing homogeneous catalyst
CN102424651A (en) * 2011-11-02 2012-04-25 台州明翔化工有限公司 Preparation method of 2,7-diacetoxy-9-fluorenone and 2,7-dyhydroxyl-9-fluorenone
CN103204781A (en) * 2013-03-14 2013-07-17 武汉大学 2, 7-bi-substituted fluorenone derivative and preparation method and application thereof
CN105330522A (en) * 2015-10-26 2016-02-17 江西师范大学 Preparation method of benzo [ b ] fluorenone series compounds
CN110194745A (en) * 2018-02-26 2019-09-03 云南大学 Fluorenes ketone compounds, preparation method and the usage
CN113173854A (en) * 2021-04-23 2021-07-27 中国科学院上海有机化学研究所 Preparation method of chiral beta-acyloxy carboxylic ester compound

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JUNLIANG WU ET AL.: "Pd-catalyzed cross-coupling of aromatic compounds with carboxylic acids via C–H bond activation", 《ORGANIC CHEMISTRY FRONTIERS》, vol. 2, no. 5, pages 502 - 505 *
KUN-KUN YU ET AL.: "Palladium-Catalyzed Diverse mono-Acyloxylation of 5-Alkyl-4-arylthiazole- 2-carboxylates", 《ASIAN JOURNAL OF ORGANIC CHEMISTRY》, vol. 5, no. 10, pages 1219 - 1224 *
杨文勇等: "２，７－二羟基－９－芴酮的合成工艺研究", 《武汉理工大学学报》, vol. 35, no. 08, pages 34 - 38 *

Also Published As

Publication number Publication date
CN115028522B (en) 2023-10-24

Similar Documents

Publication Publication Date Title
US9321744B1 (en) Method for preparing 2,5-furan dicarboxylic acid
CN115124465A (en) Preparation method of quinclorac intermediate
CN112062671B (en) Preparation method of R- (+) -2- (4-hydroxyphenoxy) propionic acid
CN115028522A (en) Preparation method of 2, 7-dihydroxy-9-fluorenone
CN110734368B (en) Preparation method of buparvaquone
CN115677636B (en) Preparation method of 2, 3',4' -biphenyl tetracarboxylic dianhydride
CN112321467A (en) Preparation method of (2S,3R) -p-methylsulfonylphenylserine ethyl ester
CN108299466B (en) Improved dolutegravir synthesis method
CN102267934B (en) Method for preparing 6-carbomethoxy indolone
CN115594639A (en) Synthesis method of key intermediate of Tegolrazan
CN115490657A (en) Preparation method of 3,3', 4' -benzophenone tetracarboxylic dianhydride
CN115536593A (en) Scalable production method of 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-formamide
CN116239465B (en) Preparation method of 4,4' -diphenyl ether diformyl chloride
NO137597B (en) XANTONE DERIVATIVES FOR USE AS INTERMEDIATE PREPARATIONS
CN112358380B (en) Synthesis method of 4- (4' -alkylcyclohexyl) cyclohexanol
CN116332889B (en) Preparation method of 3,3',4' -benzophenone tetracarboxylic dianhydride
CN115745782B (en) Preparation method and production method of phthalic acid derivative
CN116284020B (en) Preparation method of pranoprofen
CN114956972B (en) New method for synthesizing buparvaquone
CN115894593B (en) Preparation method of dydrogesterone and intermediate thereof
WO2024087157A1 (en) Method for synthesizing key intermediate of tegoprazan
CN115626880B (en) Synthesis method of 3-nitro-5-cyano benzotrifluoride
CN102557925B (en) Method for synthesizing 2,3,3',4'-diphenyl ether tetracarboxylic acid
CN116621797A (en) Preparation method of 4,4' -diphenyl ether dianhydride
WO2022262768A1 (en) Hybutimibe intermediate and preparation method therefor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant