Method for producing 5-hydroxy-2-adamantanone

Abstract

To provide a simple and highly productive method for producing 5-hydroxy-2-adamantanone.SOLUTION: A method for producing 5-hydroxy-2-adamantanone includes oxidizing 2-adamantanone using mixed acid containing sulfuric and nitric acids, wherein the water concentration in the mixed acid is 4.0 mass% or less.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for producing 5-hydroxy-2-adamantanone. [Background technology]

[0002] 5-Hydroxy-2-adamantanone (HAdON) is used as an intermediate for pharmaceuticals for chronic fatigue syndrome, tuberculosis, allergic bronchial asthma, etc. In recent years, HAdON has also been used as an electronic material such as photoresist for semiconductor manufacturing. Due to its wide range of uses, the demand for HAdON is increasing.

[0003] HAdON is generally synthesized by oxidation of 2-adamantanone (AdON). For example, US Pat. No. 5,399,663 (Indian Patent Application No. 1779 / DEL / 2014) describes a method using concentrated sulfuric acid and 50% nitric acid. US Pat. No. 5,399,663 (Russian Patent No. 2104994) describes a method using concentrated sulfuric acid, 68% nitric acid, and catalytic amounts of sodium nitrite or manganese dioxide. US Pat. No. 5,399,663 (Russian Patent No. 2319688) describes a method using concentrated sulfuric acid, 66.2% nitric acid, and catalytic amounts of acetic acid. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Indian Patent Application No. 1779 / DEL / 2014 [Patent Document 2] Russian Patent No. 2104994 [Patent Document 3] Russian Patent No. 2319688 Summary of the Invention [Problem to be solved by the invention]

[0005] A problem with the conventional technology is that the reaction of converting AdON to HAdON is slow, resulting in low productivity. For example, Patent Document 1 reports a reaction time of 12 hours, Patent Document 2 reports a reaction time of 8 to 10 hours, and Patent Document 3 reports a reaction time of 12 hours. Therefore, there is a need for a highly productive method for producing HAdON.

[0006] An object of the present invention is to provide a method for producing HAdON simply and easily with high productivity. [Means for solving the problem]

[0007] The inventors have discovered that in a method for producing HAdON by oxidizing AdON using a mixed acid (a mixture containing sulfuric acid and nitric acid), the reaction rate can be increased by controlling the amount of water mixed into the reaction system to a low level, and as a result, they have established a method for producing HAdON simply and with high productivity.

[0008] The present disclosure includes the following aspects. [Aspect 1] A method for producing 5-hydroxy-2-adamantanone, comprising oxidizing 2-adamantanone using a mixed acid containing sulfuric acid and nitric acid, wherein the mixed acid has a water concentration of 4.0 mass% or less. [Aspect 2] The method according to embodiment 1, wherein the nitric acid is concentrated nitric acid or fuming nitric acid. [Aspect 3] 3. The method according to embodiment 1 or 2, wherein concentrated sulfuric acid or oleum is used as the sulfuric acid. [Aspect 4] The method according to any one of aspects 1 to 3, wherein a mass ratio of the sulfuric acid to the nitric acid is 90:10 to 50:50. [Aspect 5] The method according to any one of aspects 1 to 4, wherein fuming nitric acid is used as the nitric acid, fuming sulfuric acid is used as the sulfuric acid, and a mass ratio of fuming sulfuric acid to fuming nitric acid is 90:10 to 50:50. [Aspect 6] The method according to any one of aspects 1 to 5, wherein the purity of the starting material, 2-adamantanone, is 90 to 100%. Effect of the Invention

[0009] According to the present invention, HAdON can be produced simply and with high productivity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In the present disclosure, "concentrated sulfuric acid" refers to a sulfuric acid solution (excluding fuming sulfuric acid) having a mass ratio of sulfuric acid of 90% or more.

[0011] In the present disclosure, "fuming sulfuric acid" refers to concentrated sulfuric acid with sulfur trioxide (SO3) absorbed therein. In one embodiment, the mass ratio of free SO3 in the fuming sulfuric acid is 1 to 60%.

[0012] In the present disclosure, "concentrated nitric acid" refers to a nitric acid solution having a mass ratio of nitric acid of 60% or more (excluding fuming nitric acid).

[0013] In the present disclosure, "fuming nitric acid" refers to concentrated nitric acid with nitrogen dioxide (NO2) absorbed. In one embodiment, the mass ratio of nitric acid in the fuming nitric acid is 70% or more.

[0014] The present invention provides a method for producing HAdON. In one embodiment, the method for producing HAdON includes oxidizing HAdON with a mixed acid containing sulfuric acid and nitric acid, and the water concentration in the mixed acid is 4.0 mass % or less.

[0015] The reaction scheme for the synthesis of HAdON by oxidation of AdON is shown below. [ka]

[0016] The starting material AdON can be obtained, for example, by oxidation of adamantane (Ad) using sulfuric acid. It is known that the oxidation of Ad using sulfuric acid produces resinous by-products in addition to the target product AdON (see Comparative Example 1 of JP-A-11-189564, paragraph 0003 of the specification of JP-A-2003-212810, etc.). Without being bound by any theory, it is presumed that the components of the resinous by-products include polymers in which the adamantane skeleton is linked via a hemiacetal structure (hemiketal structure) formed by the reaction of adamantanol (AdOH) generated by the oxidation of Ad with AdON. Resinous by-products having a hemiacetal structure may be oxidized in competition during the oxidation reaction of AdON, which may result in a slower oxidation reaction of AdON to HAdON. Therefore, it is preferable that the starting material AdON does not substantially contain the above-mentioned resinous by-products. In particular, the purity of AdON is preferably 70% or more, for example, 90 to 100%, more preferably 95 to 100%, and even more preferably 98 to 100%.

[0017] The mixed acid includes sulfuric acid and nitric acid.

[0018] As the sulfuric acid, it is preferable to use concentrated sulfuric acid or fuming sulfuric acid, and it is more preferable to use fuming sulfuric acid. Since SO3 in fuming sulfuric acid has a dehydrating effect, it is possible to effectively reduce the amount of water in the reaction system.

[0019] As the nitric acid, it is preferable to use concentrated nitric acid or fuming nitric acid, and it is more preferable to use fuming nitric acid.

[0020] The mixed acid preferably comprises fuming sulfuric acid and fuming nitric acid, since the water concentration in the mixed acid can be effectively reduced.

[0021] The water concentration in the mixed acid is 4.0% by mass or less. This increases the rate of the oxidation reaction of AdON, and allows HAdON to be produced with high productivity. The water concentration in the mixed acid is preferably 3.5% by mass or less, more preferably 3.0% by mass or less, and even more preferably 2.5% by mass or less. The lower limit of the water concentration in the mixed acid is not particularly limited, but may be, for example, 0.5% by mass or 1.0% by mass.

[0022] The mass ratio of sulfuric acid to nitric acid is not particularly limited, but can be, for example, sulfuric acid:nitric acid=90:10 to 50:50, preferably 90:10 to 70:30, more preferably 90:10 to 80:20. In an embodiment in which the nitric acid is fuming nitric acid and the sulfuric acid is concentrated sulfuric acid or fuming sulfuric acid, the mass ratio of concentrated sulfuric acid or fuming sulfuric acid to fuming nitric acid (concentrated sulfuric acid or fuming sulfuric acid:fuming nitric acid) is preferably 90:10 to 50:50, more preferably 90:10 to 70:30, and even more preferably 90:10 to 80:20. The mass ratio specified here is a value based on the mass of the active ingredients (sulfuric acid and nitric acid) and does not include the mass of water.

[0023] The AdON concentration in the reaction system at the start of the reaction is not particularly limited, but can be, for example, 1% by mass to 15% by mass, 2% by mass to 10% by mass, or 3% by mass to 8% by mass.

[0024] The amount of the mixed acid used is set so that nitric acid is preferably 1 mol to 100 mol, more preferably 1 mol to 50 mol, and even more preferably 1 mol to 30 mol per mol of AdON. By setting the amount of the mixed acid used within the above range, it is possible to increase the productivity of HAdON by the oxidation reaction of AdON while suppressing side reactions, thereby increasing the yield and purity of HAdON.

[0025] The water concentration in the reaction system is preferably 3.5% by mass or less, more preferably 3.0% by mass or less, and even more preferably 2.5% by mass or less. By setting the water concentration in the reaction system within the above range, the rate of the oxidation reaction of AdON can be increased, and HAdON can be produced with high productivity. The lower limit of the water concentration in the reaction system is not particularly limited, but can be, for example, 0.5% by mass or 1.0% by mass.

[0026] The reaction temperature can generally be in the range of 10°C to 60°C, and is preferably in the range of 20°C to 40°C.

[0027] The reaction time can generally be 10 minutes to 8 hours, preferably 20 minutes to 6 hours, and more preferably 0.5 hours to 4 hours.

[0028] The reaction can be carried out, for example, by the following procedure: Dissolve AdON in sulfuric acid. Add nitric acid dropwise to the sulfuric acid solution of AdON under ice cooling. Heat the reaction system to a predetermined reaction temperature and stir for a predetermined reaction time to complete the reaction.

[0029] After the reaction is completed, the reaction solution is neutralized in a conventional manner, and the product is extracted. The solvent is then distilled off, and the desired HAdON can be obtained by conventional purification procedures, such as recrystallization.

[0030] Examples of the neutralizing agent for the reaction solution include an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, and an aqueous solution of ammonia. The yield of HAdON can be increased by using an aqueous solution of sodium hydroxide as the neutralizing agent. Without being bound by any theory, it is believed that the type of sulfate salt produced by the reaction of the neutralizing agent with sulfuric acid affects the extraction efficiency, and that sodium salts act more favorably on the extraction efficiency.

[0031] The product can be extracted using an organic solvent such as hexane or dichloromethane. If it is desired to obtain HAdON of higher purity, it is advantageous to perform multi-stage extraction using two or more kinds of extraction solvents. For example, after removing unreacted AdON and other by-products using hexane, the aqueous layer after hexane extraction can be further extracted with dichloromethane to obtain high-purity HAdON.

[0032] The reaction solution may be diluted with water before neutralization. By diluting the reaction solution with water before neutralization, the neutralization conditions can be made milder and the production of by-products such as 2,6-adamantanedione can be suppressed, thereby further increasing the purity of HAdON.

[0033] Although the embodiments of the present invention have been described above, the present invention is not limited to these. The technical scope of the present invention is defined only by the claims. The present invention can be modified, for example, the constituent elements of the present invention can be added, deleted, and replaced, provided that the modification does not deviate from the spirit of the present invention. For example, the materials used, various conditions, etc. can be appropriately modified without departing from the spirit of the present invention. EXAMPLES

[0034] The present invention will be described in more detail below with reference to examples, but these are not intended to limit the present invention in any way.

[0035] The yield and purity of HAdON were determined by gas chromatography (GC) under the following conditions. GC device: GC-2010Plus (manufactured by Shimadzu Corporation) Column: DB-1 (Agilent Technologies, Inc.) Detector: FID Heating profile: Heat from 100°C to 280°C at a rate of 5°C / min, and hold for 4 minutes Carrier gas: Helium Split ratio: 50

[0036] The purity of the AdON used in the examples was 98%.

[0037] Example 1 26.45g (0.26mol) of 98% sulfuric acid and 3.32g (0.02mol) of AdON were added to a 100mL three-neck flask and dissolved. Then, 9.23g (0.14mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1 hour. After the reaction was completed, the reaction solution was neutralized with an aqueous ammonia solution and extracted three times with dichloromethane (20mL). The solvent was distilled off with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 59.6% (purity 71.5%).

[0038] Example 2 26.14g (0.26mol) of 98% sulfuric acid and 3.31g (0.02mol) of AdON were added to a 100mL three-neck flask and dissolved. Then, 9.26g (0.14mol) of fuming nitric acid was added dropwise under ice cooling. After the addition, the reaction system was heated to 35°C and stirred for 2 hours. After the reaction was completed, the reaction solution was neutralized with an aqueous ammonia solution and extracted three times with dichloromethane (20mL). The solvent was removed with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 67.2% (purity 79.3%).

[0039] Example 3 44.96g (0.45mol) of 98% sulfuric acid and 3.33g (0.02mol) of AdON were added to a 100mL three-neck flask and dissolved. Then, 8.77g (0.14mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was neutralized with an aqueous ammonia solution. Next, unreacted AdON and other by-products were extracted into hexane (20mL), and the aqueous layer after hexane extraction was extracted three times with dichloromethane (20mL). The solvent was distilled off with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 42.1% (purity 94.7%).

[0040] Example 4 29.99g (0.30mol) of 98% sulfuric acid and 3.31g (0.02mol) of AdON were added to a 100mL three-neck flask and dissolved. Then, 22.33g (0.34mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was neutralized with an aqueous ammonia solution. Next, unreacted AdON and other by-products were extracted into hexane (20mL), and the aqueous layer after hexane extraction was extracted three times with dichloromethane (20mL). The solvent was distilled off with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 42.9% (purity 94.0%).

[0041] Example 5 101.99g (1.02mol) of 98% sulfuric acid and 6.59g (0.04mol) of AdON were added to a 100mL three-neck flask and dissolved. Then, 17.66g (0.27mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was diluted with 99.11g of water and neutralized with an aqueous ammonia solution. Next, unreacted AdON and other by-products were extracted into hexane (40mL), and the aqueous layer after hexane extraction was extracted three times with dichloromethane (40mL). The solvent was distilled off with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 34.8% (purity 97.3%).

[0042] Example 6 In a 100mL three-neck flask, 101.80g (1.02mol) of 98% sulfuric acid and 6.65g (0.04mol) of AdON were added and dissolved. Then, 17.63g (0.27mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was diluted with 97.24g of water and neutralized with an aqueous sodium hydroxide solution. Next, unreacted AdON and other by-products were extracted into hexane (40mL), and the aqueous layer after hexane extraction was extracted three times with dichloromethane (40mL). The solvent was distilled off with an evaporator to obtain a solid. The yield of HAdON was calculated by gas chromatography analysis of the solid, and was 39.7% (purity 97.9%).

[0043] Example 7 In a 2L separable flask equipped with a stirring blade, 1556.03g (15.55mol) of 98% sulfuric acid and 101.24g (0.67mol) of AdON were added and dissolved. Then, 275.45g (4.24mol) of fuming nitric acid was added dropwise under ice cooling. After the dropwise addition, the reaction system was heated to 35°C and stirred for 1.5 hours. After the reaction was completed, the reaction solution was diluted with 1500g of water and neutralized with 10.8kg of aqueous sodium hydroxide solution. Next, unreacted AdON and other by-products were extracted twice into hexane (3.3L), and the aqueous layer after hexane extraction was extracted six times with dichloromethane (700mL). The solvent was distilled off with an evaporator to obtain a solid content. The yield of HAdON was calculated by gas chromatography analysis of the solid content and was 49.2% (purity 96.3%).

[0044] The conditions and results of Examples 1 to 7 are shown in Table 1. The conditions and results of Patent Document 1 (Indian Patent Application No. 1779 / DEL / 2014) as Comparative Example 1, Patent Document 2 (Russian Patent No. 2104994) as Comparative Example 2, and Patent Document 3 (Russian Patent No. 2319688) as Comparative Example 3 are relisted in Table 1.

[0045] [Table 1]

[0046] The results of Examples 1 to 7 show that by setting the water concentration in the mixed acid to 4.0 mass% or less, HAdON can be produced in a significantly shorter reaction time (1 to 2 hours) than in Comparative Examples 1 to 3. It is also shown that the purity of HAdON can be increased by performing multi-stage extraction using two or more types of extraction solvents (hexane and dichloromethane) (Examples 3 to 7). The purity of HAdON can be further increased by diluting the reaction solution with water before extraction (Examples 5 to 7). The yield of HAdON can be increased by using NaOH as a neutralizing agent for the reaction solution (Examples 6 to 7). [Industrial Applicability]

[0047] The method of the present invention makes it possible to produce HAdON, which is used as a pharmaceutical intermediate, electronic material, etc., simply and with high productivity.

Claims

1. A method for producing 5-hydroxy-2-adamantanone, comprising oxidizing 2-adamantanone with a mixed acid containing sulfuric acid and nitric acid, wherein the mixed acid has a water concentration of 4.0 mass% or less.

2. 2. The method according to claim 1, wherein the nitric acid is concentrated nitric acid or fuming nitric acid.

3. 3. The method according to claim 1 or 2, wherein concentrated sulfuric acid or oleum is used as said sulfuric acid.

4. The method according to claim 1 or 2, wherein the mass ratio of the sulfuric acid to the nitric acid is from 90:10 to 50:

50.

5. 3. The method according to claim 1, wherein the nitric acid is fuming nitric acid, the sulfuric acid is fuming sulfuric acid, and the mass ratio of the fuming sulfuric acid to the fuming nitric acid is 90:10 to 50:

50.

6. 3. The method according to claim 1, wherein the purity of the starting material 2-adamantanone is 90 to 100%.

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