JP2006199627A - Method for producing 9-fluorenone-2-carboxylic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high-purity 9-fluorenone-2-carboxylic acid useful as a raw material for medicines by using an inexpensive raw material which is readily industrially available. <P>SOLUTION: The method for producing the 9-fluorenone-2-carboxylic acid comprises oxidizing 2-acetylfluorene with molecular oxygen in an aliphatic carboxylic acid such as acetic acid in the presence of a catalyst containing a heavy metal component such as cobalt and manganese and a bromine component under conditions of 80-180°C reaction temperature and 0.5-5 MPa reaction pressure. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing 9-fluorenone-2-carboxylic acid useful as a pharmaceutical raw material.

  Conventionally, as a method for producing 9-fluorenone-2-carboxylic acid using 2-acetylfluorene as a raw material, oxidation with sodium dichromate (Non-patent Document 1) and oxidation with potassium hypochlorite (Non-patent Document 2) are available. Are known. In the former method, there is a problem in that the volumetric efficiency of the reaction is poor and it is necessary to treat a chromium waste solution that is environmentally problematic. Although the latter method has an advantage that the target product can be obtained with a relatively high yield, there is a problem that it is difficult to industrially obtain potassium hypochlorite used as an oxidizing agent.

Organic Synthesis, CODEN: ORSYAT, Coll. Vol. III, P23 (1955) Journal of American Chemical Society, Vol.70, P3958 (1948)

  Accordingly, an object of the present invention is to provide a method for producing 9-fluorenone-2-carboxylic acid in a high yield by using raw materials that are industrially easily available.

  That is, according to the present invention, there is provided a method for producing 9-fluorenone-2-carboxylic acid, characterized in that 2-acetylfluorene is oxidized with molecular oxygen. In this oxidation, a catalyst containing a heavy metal component and a bromine component is preferably used, and an aliphatic carboxylic acid is preferably used as a reaction solvent.

  According to the present invention, it is possible to produce 9-fluorenone-2-carboxylic acid having a high purity with a high yield using industrially easily available and inexpensive raw materials.

  In the present invention, 2-acetylfluorene is oxidized with molecular oxygen to produce 9-fluorenone-2-carboxylic acid. The 2-acetylfluorene used as the raw material may be produced by any method, but industrially, it is preferably obtained by a method in which fluorene is reacted with acetyl chloride or acetic anhydride.

  In the oxidation reaction of 2-acetylfluorene, it is preferable to use a catalyst containing a heavy metal component and a bromine component. Examples of the heavy metal component include one or two or more metal components such as cobalt, manganese, cerium, and nickel, but it is particularly preferable to use at least one metal component selected from cobalt and manganese. A particularly preferred heavy metal component is cobalt or a mixed manganese / metal heavy metal component having a ratio of 0.01 to 2 gram atoms of manganese to 1 gram atom of cobalt. The heavy metal component is preferably used in the form of a compound. For example, oxides, hydroxides, carbonates, halides, carboxylates, acetylacetonates and the like can be used. In particular, the use of carboxylates and bromides such as acetates and naphthenates is preferred. Bromine components include bromine, hydrogen bromide, cobalt bromide, manganese bromide, ammonium bromide, sodium bromide, potassium bromide and other inorganic bromine compounds, tribromoethane, tetrabromoethane, bromoacetic acid, bromide. Organic bromine compounds such as benzyl can be used. Specific examples of the catalyst containing a heavy metal component and a bromine component include, for example, cobalt acetate and potassium bromide, cobalt bromide and manganese acetate, cobalt acetate and manganese bromide, cobalt acetate, manganese acetate and ammonium bromide, cobalt acetate and acetic acid. Examples of the combined catalyst include manganese and sodium bromide, cobalt acetate, manganese acetate and potassium bromide, cobalt naphthenate, manganese naphthenate and hydrogen bromide, cobalt acetylacetonate, manganese acetylacetonate and potassium bromide. However, it is not limited to these combinations.

  The oxidation reaction of 2-acetylfluorene is also preferably performed in a solvent. In consideration of operability and reaction yield, it is preferable to use an aliphatic carboxylic acid that exhibits a liquid state under the reaction conditions, such as acetic acid, propionic acid, butyric acid, and the like. These can be used alone or as a mixture. A particularly preferred solvent is acetic acid, propionic acid, or a mixture thereof, and most preferred is acetic acid. When such an aliphatic carboxylic acid is used as a solvent, other solvents can be used in combination as long as the reaction is not significantly impaired. For example, there is no particular problem even if an aliphatic carboxylic acid containing about 5% by weight or less of water in the total solvent is used as the solvent.

  The solvent is preferably used in an amount of about 3 to 20 times, especially about 5 to 15 times the weight of 2-acetylfluorene. Further, the heavy metal component is preferably 0.01% by weight or more, particularly 0.05 to 1% by weight of the solvent in terms of metal, and 0.005 to 0.5 gram atom per mole of 2-acetylfluorene. In particular, it should be used at a ratio of 0.01 to 0.1 gram atom. Further, the bromine component is preferably used at a ratio of 0.1 to 10 gram atoms, particularly 0.2 to 5 gram atoms, as bromine atoms with respect to 1 gram atom of heavy metal.

  As molecular oxygen which is an oxidizing agent, an oxygen-containing gas having an arbitrary concentration such as pure oxygen, air, or combustion exhaust gas can be used, but air is usually used.

  As a reaction method, 2-acetylfluorene as a raw material and a catalyst solution in which an oxidation catalyst is dissolved in a solvent are charged in advance in a reactor, and only a molecular oxygen is continuously supplied to react. A semi-continuous system in which only the catalyst solution is charged into the reactor and the raw material and molecular oxygen are continuously supplied and reacted, or each of the raw material, catalyst solution, and molecular oxygen is continuously supplied to the reactor. It is possible to carry out any of the continuous systems in which the reaction solution is supplied and reacted, and the reaction solution is continuously extracted.

  The reaction temperature in the oxidation reaction is preferably in the range of 80 to 180 ° C, particularly 120 to 150 ° C. That is, if the reaction temperature is too low, the reaction rate tends to be slow, and if the reaction temperature is too high, the degree of coloration of the product tends to increase. The reaction pressure in the oxidation reaction may be a pressure that can maintain the reaction liquid in a liquid state, and varies depending on the reaction temperature, but is usually about 0.5 to 5 MPa, preferably about 1 to 3 MPa. The reaction time in the oxidation reaction varies depending on the reaction conditions such as the amount of catalyst and reaction temperature, but is generally about 1 to 10 hours, preferably about 1 to 6 hours.

  The 9-fluorenone-2-carboxylic acid produced by the oxidation reaction is precipitated by cooling the reaction solution after the reaction is completed, so pressure-type filtration devices such as filter presses, screw presses, belt presses, etc., rotating cylindrical types It can be recovered by filtration, separation, and the like using a vacuum filtration device such as a filter and a rotary disk filter, a centrifugal filter such as a screw type and a basket type. The 9-fluorenone-2-carboxylic acid crystal recovered in this manner can be generally made into a product by washing with water or aliphatic carboxylic acid and then drying. In this case, it can refine | purify by adding operation, such as acid precipitation, crystallization, extraction, as needed.

Hereinafter, the present invention will be described in more detail with reference to examples. The analysis of 9-fluorenone-2-carboxylic acid was performed by high performance liquid chromatography under the following conditions, and quantification was performed by an absolute calibration curve method using a reagent manufactured by Aldrich as a standard substance.
Measurement conditions Column: ODS-2 (manufactured by GL Sciences) length 150 mm, inner diameter 4.6 mm
Mobile phase: A = acetonitrile / tetrahydrofuran (75/25 volume ratio)
B = 70% perchloric acid / water (2.0 ml / L)
Mobile phase ratio: A / B = (40/60 volume ratio)
Detector: UV (254 nm)
Flow rate: 1.0 ml / min Column temperature: 40 ° C

[Example 1]
A titanium autoclave with an internal volume of 500 ml equipped with a stirrer, a gas blowing pipe, an exhaust gas extraction pipe with a reflux condenser, a raw material introduction pipe and a thermometer, 25 g of 2-acetylfluorene having a purity of 99.8% by weight and a water content of 0.2 250% by weight of glacial acetic acid, 0.90 g of cobalt acetate tetrahydrate, 0.88 g of manganese acetate tetrahydrate and 0.86 g of potassium bromide were charged.

  After replacing the atmosphere with nitrogen, the mixture was heated to 150 ° C. with stirring, and then air was introduced through the gas blowing tube so that the exhaust gas flow rate became 1.5 liters / minute, and the reaction system was The temperature was kept at 150 ° C. and the pressure was 1.0 MPa, and the reaction was continued for about 65 minutes until the absorption of oxygen disappeared.

  After the introduction of air was stopped, the autoclave was cooled. After cooling, the contents were taken out and the crystals were separated by filtration to obtain a 9-fluorenone-2-carboxylic acid cake and filtrate. The obtained cake was washed with the same volume of acetic acid and then vacuum-dried to obtain 17.9 g of yellow 9-fluorenone-2-carboxylic acid. The purity determined by liquid chromatography was 99.2% by weight, and the yield was 65.9% by mole.

[Example 2]
The same operation as in Example 1 was carried out except that the reaction temperature was changed to 180 ° C., to obtain 18.2 g of a slightly brownish yellow 9-fluorenone-2-carboxylic acid. The purity determined by liquid chromatography was 99.2% by weight, and the yield was 67.1 mol%.

[Example 3]
A titanium autoclave with an internal volume of 50 liters equipped with a stirrer, a gas blowing pipe, an exhaust gas extraction pipe with a reflux condenser, a raw material introduction pipe and a thermometer, 2.5 kg of 2-acetylfluorene having a purity of 90.7% by weight, moisture 25 kg of glacial acetic acid containing 0.2% by weight, 0.90 kg of cobalt acetate tetrahydrate, 0.88 kg of manganese acetate tetrahydrate and 0.86 kg of potassium bromide were charged.

  After substituting the atmosphere with nitrogen, the mixture was heated to 150 ° C. with stirring, and then air was introduced through the gas blowing tube so that the exhaust gas flow rate was 40 liters / minute, and the reaction system was heated to 150 ° C. The reaction was continued for about 2 hours until the absorption of oxygen was stopped.

After the introduction of air was stopped, the autoclave was cooled. After cooling, the contents were taken out and the crystals were separated by filtration to obtain a 9-fluorenone-2-carboxylic acid cake and filtrate. The obtained cake was washed with the same volume of acetic acid and then vacuum-dried to obtain 1.57 kg of yellow 9-fluorenone-2-carboxylic acid. The purity determined by liquid chromatography was 97.9 wt%, and the yield was 63.1 mol%.

Claims (3)

  A process for producing 9-fluorenone-2-carboxylic acid, characterized in that 2-acetylfluorene is oxidized with molecular oxygen.   The method for producing 9-fluorenone-2-carboxylic acid according to claim 1, wherein the oxidation is carried out in the presence of a catalyst containing a heavy metal component and a bromine component.   The method for producing 9-fluorenone-2-carboxylic acid according to claim 1 or 2, wherein the oxidation is carried out in an aliphatic carboxylic acid.