JP2005306837A - Method for producing adamantanols - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To produce an adamantanol industrially useful as a medicine or a monomer for photoresist by a simple process to mildly oxidizing adamantanes with a nitrous acid salt or a nitric acid salt without producing adamantanediols. <P>SOLUTION: The method for the production of adamantanols comprises the oxidation of adamantanes with a nitrous acid salt or a nitric acid salt in the presence of a strong acid having an acid dissociation constant (pKa) of ≤1 in an aqueous solution, preferably trifluoroacetic acid, methanesulfonic acid, etc., and the hydrolysis of the produced acid ester of adamantanols. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  In the present invention, an adamantane is oxidized with nitrite or nitrate in the presence of a strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution of trifluoroacetic acid, methanesulfonic acid, etc. The present invention relates to a method for producing adamantanols by hydrolyzing esters.

  1-Adamantanol, such as 1-adamantanol, adamantanols formed by bonding one hydroxyl group are pharmaceutical intermediates, raw materials for photoresist monomers, raw materials for photochromic dyes, paints, adhesives, adhesives, coating materials, etc. It is an extremely important compound industrially as a raw material of the material.

  As a conventional method for producing adamantanols, a method of oxidizing adamantane with various oxidizing agents is known. For example, a method of performing oxygen oxidation in the presence of a vanadium catalyst and an imide compound (see Patent Document 1), a ruthenium catalyst, and the like. A method of oxidizing with hypochlorous acid in the presence (see Patent Document 2) and the like are known.

  However, in this method, not only adamantanol but also adamantanediol and the like are by-produced in large quantities, so that a complicated separation operation is required to obtain the target adamantanol. On the other hand, as a method of producing only adamantanol, a method of oxidizing with ozone in an organic solvent (see Patent Document 3) is known.

  However, since the above method uses ozone as an oxidant, a special apparatus such as an ozone generator must be used for the reaction, and the yield of 1-adamantanol obtained in the examples is obtained. The highest is only 62%, and it is hard to say that the yield is very satisfactory.

  For this reason, development of the method of manufacturing adamantanol which does not produce | generate a high yield and a large amount of waste liquid using a simple apparatus was strongly desired.

  On the other hand, the oxidation reaction using nitric acid or nitrate is one of the most important oxidation reactions for organic synthesis, and is a general method for oxidizing an aliphatic cyclic secondary alcohol compound to an aliphatic dicarboxylic acid derivative. It is.

  However, there are few examples of oxidation reactions using nitric acid or nitrates for the oxidation of aliphatic hydrocarbons having a diamond skeleton such as adamantane, and in recent years oxidation reactions of adamantane with nitronium trifluoroborate are known (non- Patent Document 1).

  However, the main product by the above method is nitroadamantane, and the yield of 1-adamantanol is only about 10%. By the oxidation of nitric acid or nitrate of adamantane known before, 1-adamantane is obtained. There have been no reports of cases in which tanol can be obtained as a main product in high yield.

  Under such circumstances, the present inventors focused on a method of oxidizing an alcohol compound into an aldehyde compound or a ketone compound using sodium nitrite or sodium nitrate in a 90% aqueous trifluoroacetic acid solution (see Non-Patent Document 2).

Japanese Patent Laid-Open No. 10-316601 JP 2000-219646 A JP 2004-26778 A Journal of Amercan Chemical Society Vol. 115, 7246-7249, 1993 (Journal of American Chemical Society, 115, 7246-7249 (1993)) Zanal Organicheskoi Khimii, 24, 488-495, 1988 (Zhurnal Organicheskoi Khimii, 24, 488-495 (1988))

  The above method is a mild oxidation reaction in which sodium nitrite or sodium nitrate is used in an equimolar amount or more with an alcohol compound at room temperature under an open atmosphere. However, the method described above is limited to a method of oxidizing a primary or secondary alcohol compound to an aldehyde compound or a ketone compound, and no mention is made regarding oxidation of an aliphatic hydrocarbon having a diamond skeleton such as adamantane. . Accordingly, it has been completely unknown to those skilled in the art whether this mild nitric acid oxidation method can be applied to a method for producing adamantanols from adamantanes.

  In the background described above, the present invention provides a method for obtaining the target compound in a high yield and high selectivity by a simple method in a method for producing adamantanols by oxidizing adamantanes as raw materials. Objective.

  In view of this situation, the present inventors have intensively studied whether or not the mild nitric acid oxidation can be applied to the oxidation of adamantanes. As a result, adamantanes are oxidized with nitrite or nitrate in the presence of a strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution typified by trifluoroacetic acid, and then once adamantanols with the above strong acids are obtained. After producing an acid ester, a method for obtaining adamantanol with high yield by hydrolyzing the acid ester was found, and the present invention was completed.

  That is, the present invention is characterized in that an adamantane is oxidized with nitrite or nitrate in the presence of a strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution, and then the resulting acid ester is hydrolyzed. This is a method for producing a tanol.

  According to the present invention, an adamantane is oxidized with nitrite or nitrate to obtain an acid ester of an adamantanol, and then a high yield, high yield is obtained by a simple method of hydrolyzing the acid ester of the generated adamantanol. The target adamantanols can be obtained with selectivity. Accordingly, high-purity adamantanols can be obtained without complicated separation operations, which is extremely useful industrially.

  In the present invention, adamantane refers to a compound in which at least one of the four tertiary carbons on the adamantane skeleton, that is, the 1-position, 3-position, 5-position and 7-position carbon atoms is unsubstituted, in addition to adamantane. Usually, those represented by the following general formula (I) are used.

(In the formula, R is an alkyl group, an aryl group, or an aralkyl group, and n is an integer of 0 to 3.
)
In the general formula (I), the alkyl group of R is not particularly limited, but those having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group and butyl group are preferable. The aryl group preferably has 6 to 10 carbon atoms such as a phenyl group. The aralkyl group preferably has 7 to 12 carbon atoms such as a benzyl group.

  When a plurality of Rs are substituted with respect to the adamantane skeleton, these may be the same or different.

  Specific examples of the adamantanes represented by the general formula (I) include adamantane, 1-methyladamantane, 1-ethyladamantane, 2-methyladamantane, 2-ethyladamantane, 1,3-dimethyladamantane, 1,3 -Alkyladamantanes such as diethyl adamantane, 1,2-dimethyladamantane, 1,2-diethyladamantane; aryladamantanes such as 1-phenyladamantane; aralkyladamantanes such as 1-benzyladamantane, and the like.

  Among these adamantanes, adamantane, 1-methyladamantane, 1,3-dimethyladamantane, 1-phenyladamantane and the like are particularly preferably used for reasons such as reactivity and availability.

  As nitrite and nitrate used in the present invention, industrially or easily available compounds as reagents are used without any limitation. Specifically, as the nitrite, sodium nitrite, potassium nitrite, lithium nitrite, silver nitrite and the like can be used, and as the nitrate, ammonium nitrate, ammonium cerium nitrate, lithium nitrate, potassium nitrate, sodium nitrate, nitric acid Examples thereof include cesium, nickel nitrate, samarium nitrate, strontium nitrate, silver nitrate, zinc nitrate, copper nitrate, and lead nitrate. Among these nitrites and nitrates, nitrites that generate nitric oxide cations having high oxidizing power in the reaction system show high reaction yields and are therefore preferably used in the present invention. In particular, alkali metal salts of nitrous acid such as sodium nitrite, potassium nitrite, and lithium nitrite can achieve the above-mentioned object to a high degree and are more preferable.

  The amount of nitrite or nitrate used in the present invention cannot be generally described because it varies depending on the oxygen concentration of the reaction atmosphere. However, if the amount is too small, the oxidation reaction does not proceed. Therefore, it is usually employed in the range of 0.001 to 4 mol, preferably 0.005 to 2 mol, with respect to 1 mol of adamantanes usually used in the reaction. When oxygen is not contained in the reaction atmosphere, an attempt to react substantially all of the raw material adamantanes requires an equimolar amount or more of nitrite or nitrate, but oxygen is contained in the atmosphere. In this case, nitrite and nitrate act as a catalyst, and even if the amount used is less than 1 mole per 1 adamantane, the reaction can be carried out in a high yield, which is efficient. In particular, when the oxygen concentration in the reaction atmosphere exceeds 15%, nitrite and nitrate act extremely effectively as a catalyst, and therefore usually 0.001 to 0.5 mole, preferably 1 mole relative to 1 mole of adamantane used. It can be employed in the range of 0.005 to 0.4 mol, and is preferable from the viewpoints of economy and purification of the product.

  A strong acid having an acid dissociation constant (pKa) in an aqueous solution of 1 or less used in the present invention can be used by reacting a solid acid such as trichloroacetic acid at a temperature higher than the melting point. In general, a liquid at room temperature is also used as a solvent. Examples of such strong acids include trifluoroacetic acid (pKa = 0.23), methanesulfonic acid (pKa = −1.86), trifluoromethanesulfonic acid (pKa = −13), and among these, trifluoroacetic acid. Alternatively, methanesulfonic acid, particularly trifluoroacetic acid is preferably used from the viewpoint of reactivity. The amount of these strong acids to be used is not particularly limited. However, if the amount is too small, the yield of the oxidation reaction is reduced, and if the amount is too large, the post-treatment operation becomes complicated. It is preferable to use an amount of 05 to 60% by mass, preferably 0.1 to 30% by mass.

  A strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution used in the present invention is usually used in an anhydrous state. Even if a small amount of water is mixed, there is not much influence on the oxidation reaction, but if too much water is mixed, it acts as an inhibitor of the oxidation reaction and the amount of nitrite or nitrate that is an oxidant must be increased. In the reaction solution, the content of water is preferably 5% by mass or less, preferably 1% by mass or less. In general, the most common method is to use the above strong acids available as reagents or industrial raw materials as they are.

  The reaction temperature of nitric acid oxidation in the present invention is not particularly limited, but if the temperature is too high, the oxidation reaction will run away and the reaction system will be in a dangerous state. It is good to carry out in the range of -50 degreeC above, Preferably 0-40 degreeC.

  The reaction time of this reaction varies depending on the type of adamantane and also varies depending on the type and amount of nitrite or nitrate to be used, so that usually 0.1 to 30 hours is sufficient.

  The present invention can be implemented in any state of normal pressure, reduced pressure, and increased pressure. The present invention can be carried out not only in the presence of oxygen such as oxygen and air, but also in the presence of an inert gas such as nitrogen, argon, carbon dioxide, etc., but in the presence of oxygen, nitrite or nitrate is used. Since the amount tends to be reduced and the reaction time tends to be shortened, it is generally carried out in an air or oxygen atmosphere.

  The acid esters of the adamantanols thus obtained with strong acids having an acid dissociation constant (pKa) in the aqueous solution of 1 or less can be isolated as they are and used as various industrial raw materials. It is preferable to transfer to a hydrolysis step and use it for the production of adamantanols. At this time, the acid ester may or may not be isolated from the reaction solution.

  As a method for isolating the acid ester of adamantanols produced according to the present invention, ordinary methods can be used without any limitation. For example, after the reaction is completed, the remaining strong acid is distilled off as much as possible, neutralized with a saturated aqueous solution of carbonic acid, and extracted, dried and dried using an organic solvent incompatible with water. Can be obtained.

  The hydrolysis reaction of the acid ester of adamantanol may be performed by any method. When an acid ester of adamantanol is isolated, water may be added after dissolving the compound in an organic solvent that dissolves in water such as an alcohol solvent such as methanol or ethanol. Even when an acid ester of adamantanol is not isolated, the hydrolysis reaction proceeds by simply adding water to the reaction solution. Since the reaction may take time, in that case, an acid may be added to increase the reactivity.

  As the acid added in the present invention, an acid available as an industrial raw material or a reagent can be used without any limitation.

  Specific examples of these acids include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids include sulfones such as methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Acids; carboxylic acids such as formic acid, acetic acid and propionic acid can be mentioned. Among these acids, mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, which have a particularly fast hydrolysis reaction rate, are preferable.

  These mineral acids may be added directly after adding water. However, if the concentration is too high, a rapid exotherm occurs when brought into contact with water.

  In the present invention, the amount of water used in the hydrolysis reaction may be 1 mol or more with respect to 1 mol of the acid ester of adamantanol, but is preferably 10 mol to 1000 mol. The reaction temperature during the hydrolysis reaction is not particularly limited, but if the temperature is too low, the hydrolysis rate is remarkably reduced, and if the temperature is too high, side reactions are promoted. It is better to select from the range of ° C.

  The reaction time for the hydrolysis reaction varies depending on the type of adamantane, and therefore cannot be generally stated, but usually 1 to 40 hours is sufficient.

  In addition, the hydrolysis reaction can be carried out under normal pressure, reduced pressure, or increased pressure.

  There is no restriction | limiting in particular as an isolation production method of the adamantanol obtained in this way, A well-known method is employ | adopted. For example, after completion of the reaction, an organic solvent that is incompatible with water is added to extract reactive organisms in the organic layer, and then washed with a saturated aqueous sodium hydrogen carbonate solution. The obtained adamantanol can be obtained by drying the obtained organic solvent solution using a desiccant such as magnesium sulfate and then distilling off the organic solvent.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1
Under openness to the atmosphere, 136 mg (1 mmol) of adamantane (Wako Pure Chemicals reagent grade) as adamantanes was taken into a 50 ml cocoon flask, and 5 ml of trifluoroacetic acid (Wako Pure Chemicals reagent grade) was added and cooled to 0 ° C. . Under ice-cooling, 76 mg (1.1 mmol) of sodium nitrite (Wako Pure Chemical) was added as a nitrite. The mixture was stirred as it was for 20 minutes, then returned to room temperature and stirred for 23 hours. After completion of the reaction, 5 ml of water was added to the reaction solution, and further 3 ml of 10% hydrochloric acid was added and stirred for 12 hours. After completion of hydrolysis, 5 ml of water was further added, followed by extraction with methylene chloride (30 ml × 3). The collected methylene chloride was washed with a saturated sodium hydrogen carbonate solution (20 ml × 2) and dried over magnesium sulfate, and then the methylene chloride was distilled off to obtain 148 mg of 1-adamantanol (yield 97%). At this time, no by-product of 1,3-adamantanediol was observed.

Examples 2-7
The same operation as in Example 1 was performed except that nitrite or nitrate shown in Table 1 was used instead of sodium nitrite. The results are shown in Table 1. In these reactions, 1,3-adamantanediol by-product was not seen in any case.

Examples 8-10
The same operation as in Example 1 was performed except that adamantanes shown in Table 2 were used instead of adamantane. The results are shown in Table 2. In these reactions, 1,3-adamantanediol by-product was not seen in any case.

Example 11
The same operation as in Example 1 was performed except that the same amount of methanesulfonic acid was used instead of trifluoroacetic acid and the reaction time of the oxidation reaction was 72 hours. As a result, 131 mg (yield 89%) of 1-adamantanol was obtained. At this time, no by-product of 1,3-adamantanediol was observed.

Example 12
The same operation as in Example 1 was performed except that the amount of sodium nitrite was changed to 0.69 mg (0.01 mmol), the reaction atmosphere was changed to an oxygen atmosphere, and the reaction time of the oxidation reaction was changed to 3 hours. As a result, 140 mg (yield 92%) of 1-adamantanol was obtained. At this time, no by-product of 1,3-adamantanediol was observed.
Example 13
The same operation as in Example 1 was performed except that the amount of sodium nitrite was changed to 13.8 mg (0.2 mmol). As a result, 147 mg (yield 96%) of 1-adamantanol was obtained. At this time, no by-product of 1,3-adamantanediol was observed.

Example 14
136 mg (1 mmol) of adamantane (Wako Pure Chemical Reagent special grade) as adamantane was taken in a 50 ml cocoon flask, and 5 ml of trifluoroacetic acid (Wako Pure Chemical Reagent special grade) as a solvent was added and cooled to 0 ° C. Under ice-cooling, 76 mg (1.1 mmol) of sodium nitrite (Wako Pure Chemical) was added as a nitrite. The mixture was stirred as it was for 20 minutes, then returned to room temperature and stirred for 23 hours. After completion of the reaction, trifluoroacetic acid was distilled off under reduced pressure, 5 ml of water was added to the reaction solution, 20 ml of a saturated aqueous sodium hydrogen carbonate solution was immediately added, and then extracted with methylene chloride (30 ml × 3). The collected methylene chloride was washed with a saturated sodium bicarbonate solution (20 ml × 2) and dried over magnesium sulfate, and then the methylene chloride was distilled off to obtain 248 mg of 1-trifluoroacetoxyadamantane (yield 100%). At this time, no by-product of 1,3-ditrifluoroacetoxyadamantane was observed.

Claims (3)

  The adamantanol is characterized in that an acid ester of adamantanol is hydrolyzed after oxidation of adamantane with nitrite or nitrate in the presence of a strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution. Manufacturing method.   The method for producing adamantanols according to claim 1, wherein oxidation of adamantanes is carried out in an atmosphere containing oxygen using less than 1 mol of nitrite or nitrate with respect to 1 mol of adamantanes. A method for producing an adamantanol acid ester, comprising oxidizing adamantane with nitrite or nitrate in the presence of a strong acid having an acid dissociation constant (pKa) of 1 or less in an aqueous solution.