JPH1036324A - Production of 1-nitroadamantane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enable to obtain the subject compound useful as an intermediate raw material for antiviral medicines, antibacterial medicines, etc., in high selectivity from easily available raw materials by nitrating an adamantane derivative with a nitrogen oxide and a specific mixed gas. SOLUTION: This method for producing a 1-nitroadamantane derivative comprises nitrating (A) a compound of the formula (R is H, a halogen, an alkyl) with (B) a nitrogen oxide and (C) oxygen or air containing ozone preferably in the presence of (D) a reaction accelerator comprising an organic acid or a metal (compound) (e.g. toluenesulfonic acid, an iron chloride, an acetylacetonatoiron). The reaction is carried out e.g. in a solvent such as a halogenated aliphatic compound at a temperature of -200 to 100 deg.C, preferably -90 to -20 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for nitrating an adamantane derivative for producing a 1-nitroadamantane derivative. The 1-nitroadamantane derivative is useful as an intermediate for pharmaceuticals such as an antiviral agent (Japanese Patent Application Laid-Open No. 47-25162, 25163, German Patent No. 2232735) and an antibacterial agent (Czechoslovakian Patent No. 275143).

[0002]

2. Description of the Related Art A method for nitrating adamantane is nitronium hexafluorophosphate (Journal of the American Chemical Society,
1971, 93, 1259), a method using nitronium tetrafluoroborate (Journal of the American Chemical Society, 199)
3 years, 115, 7247), a method using nitric acid (Journal of Organic Chemistry, 196)
1 year, 26, 2207) and a method using dinitrogen pentoxide (Chemistry Letters, 1974, 1431).
Page) are known.

[0003] However, these methods use expensive and difficult-to-handle reagents, have low selectivity for 1-nitroadamantane, and have problems as a practical production method.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to obtain 1-nitroadamantane by nitrating an adamantane derivative with high selectivity using a commercially available reagent.
-To provide a process for producing nitroadamantane.

[0005]

That is, the present invention provides a compound represented by the following general formula (1):

[0006]

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An adamantane derivative represented by the formula (R represents a hydrogen atom, a halogen atom or an alkyl group) is nitrated by the action of oxygen or air containing nitrogen oxide and ozone. The present invention relates to a method for producing a nitroadamantane derivative.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the adamantane derivative as a raw material represented by the general formula (1) used in the present invention, R represents a hydrogen atom, a halogen atom or an alkyl group, wherein the halogen atom is fluorine, It is chlorine, bromine or iodine, and the alkyl group usually has 1 to 10 carbon atoms.

Specific examples include adamantane, 1
-Fluoroadamantane, 2-fluoroadamantane,
1-chloroadamantane, 2-chloroadamantane, 1
-Bromoadamantane, 2-bromoadamantane, 1-
Iodo adamantane, 2-iodo adamantane, 1-methyl adamantane, 2-methyl adamantane, 1-ethyl adamantane, 1-propyl adamantane, 2-propyl adamantane, 1-butyl adamantane, 2-butyl adamantane, 1-pentyl adamantane, 2- Pentyl adamantane, 1-hexyl adamantane, 2-hexyl adamantane, 1-heptyl adamantane, 2-
Heptyl adamantane, 1-octyl adamantane, 2
-Octyl adamantane, 1-nonyl adamantane, 2
-Nonyladamantane, 1-decyladamantane, 2-
Decyl adamantane and the like can be mentioned.

As nitrogen oxides, NO, NO ₂ , N
₂ O ₃ , N ₂ O ₄ , N ₂ O _{5 and the} like can be used alone or in combination. The amount of the nitrogen oxide used varies slightly depending on the type of the nitrogen oxide or the mixture composition ratio thereof, but is preferably 2 to 30 times the molar amount of the raw material in terms of nitrogen atoms. Ozone is obtained by passing oxygen or air through a silent discharge tube, and is used by blowing the mixed gas into a reaction system. The amount of ozone used is preferably 1 to 10 times the amount of the raw material.

Examples of the solvent include those which are stable under the reaction conditions of the present invention, for example, halogenated aliphatic compounds, sulfolane, acetonitrile, aliphatic nitro compounds and aliphatic hydrocarbons.

Examples of the halogenated aliphatic compound include methylene chloride, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane. , Pentachloroethane, 1,2-dichloropropane, 1,3
-Dichloropropane, 1,2,3-trichloropropane, 1,1,2,3-tetrachloropropane, 1,1,
3,3-tetrachloropropane, 1,1,1,2,2
3,3-heptachloropropane, 1,1,1,2,3
3,3-heptachloropropane, 1,2-dichlorobutane, 1,4-dichlorobutane and the like can be mentioned.

Examples of the aliphatic nitro compound include nitromethane and nitroethane. In addition, examples of the aliphatic hydrocarbon include n-pentane, n-hexane, n-heptane, n-octane, and the like. Further, sulfolane or acetonitrile can be used. These solvents may be used alone or as a mixture of two or more kinds, and are usually 1 to 200 times by weight, preferably 3 to 100 times by weight of the raw material.

This reaction is preferably carried out in the presence of an organic acid, a metal and / or a metal compound as a reaction accelerator.
Examples of the organic acid include organic acids such as paratoluenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid. Examples of the metal include transition metals such as copper, zinc, iron, cobalt, nickel, ruthenium, and palladium, tin,
Metals such as antimony, lead and bismuth are also used. Examples of the metal compound include oxides, hydroxides, and salts. Examples of the metal salts include halides such as chloride and bromide, and salts such as nitrate and sulfate. Further, a metal complex or the like may be used. These reaction accelerators can be used alone or in combination of two or more. In the case of complexes and salts, it is desirable to avoid those that are nitrated with nitric acid or nitrogen oxides, or organic compounds that are oxidized.

Among these metals and metal compounds, iron is preferred because it is low in cost and economical, and an extremely good result can be obtained even with a reaction promoting effect. As iron compounds,
Inorganic salts such as ferrous chloride, ferric chloride, ferrous nitrate, ferric nitrate, ferrous sulfate, and ferric sulfate; and organic salts such as iron (III) acetylacetonate and iron (III) phthalocyanine. And the like.

The amount of addition is 0.2 to 5 molar equivalents in the case of an organic acid, and 0.01 to 5 in the case of a metal and / or a metal compound.
~ 5 mol% is preferred. The reaction temperature is -200 to 1
00 ° C, preferably -100 to 50 ° C, particularly preferably -90 to -20 ° C. The formation mechanism of the product of this reaction is presumed as in the following scheme.

[0017]

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That is, the desired 1-nitroadamantane (2) and adamantanone (6) are produced by the NO ₃ radical, and the 1-adamantyl nitrate (3) and the 2-adamantyl nitrate (5) are produced by the NO ₂ ion. )) And 1-adamantanol (4). −
A large excess of nitrogen dioxide at 78 ° C significantly increases the regioselectivity of the tertiary / secondary nitration.

The completion of the reaction can be determined by analyzing the reaction solution by gas chromatography or the like. The reaction may be normal pressure or pressurized, and may be batch type or continuous type. After the reaction, if necessary, the reaction solution is neutralized, and then the purity of the target product can be efficiently increased by ordinary methods such as washing with water, distillation and crystallization.

[0020]

The present invention will be described in more detail with reference to the following examples. The present invention is not limited by these. Example 1 2.0 cm ³ (60 mmol) of liquid nitrogen dioxide was added dropwise at −78 ° C. while stirring a mixture of 0.27 g (20 mmol) of adamantane and 30 cm ³ of dichloromethane. Subsequently, oxygen gas containing 10 mmol / hour of ozone was supplied for 0.5 hour. Thereafter, an aqueous solution of sodium hydrogen carbonate was added to stop the reaction. The organic layer was separated, washed with water, and dehydrated with sodium sulfate.

When this organic layer is analyzed by gas chromatography, the composition is the compound number in the above-mentioned scheme, 1: 2: 3: 4: 5: 6 = 0: 93.9: 4.2:
It turned out to be 1.9: 0: 0. The solvent was distilled off under reduced pressure to obtain white crystals. This was further purified by alumina chromatography (eluent: hexane-ethyl acetate) to give 0.32 g (yield 90%) of the desired nitro derivative (2) [melting point: 162
１６163 ° C. (Tetrahedron Letter, 1986, 2
7, 2335; 159 ° C.).

Examples 2 to 11 Table 1 summarizes the results of the same reaction operation as in Example 1, except that the reaction temperature, the amount of nitrogen dioxide, the amount of ozone, the reaction time and the like were changed.

[0023]

[Table 1]

Comparative Examples 1 to 4 The same reaction procedures were performed as in Example 1, except that the reaction conditions were changed. Table 2 shows the results.

[0025]

[Table 2]

Claims (2)

[Claims] 1. A compound of the general formula (1) (R represents a hydrogen atom, a halogen atom or an alkyl group.) 1-nitroadamantane derivative characterized by nitrating the adamantane derivative represented by the formula (1) with oxygen or air containing nitrogen oxide and ozone. Manufacturing method. 2. The method for producing a 1-nitroadamantane derivative according to claim 1, wherein an organic acid, a metal and / or a compound of the metal is used as a reaction accelerator.