JP2001335528A - Method for producing 6-acyl-2-substituted naphthalenes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily and selectively producing a 6-acyl-2- substituted naphthalene in a high yield. SOLUTION: This method for producing a 6-acyl-2-substituted naphthalene is characterized by comprising the reaction of the corresponding 2-substituted naphthalene with an acylating agent in the presence of an acid catalyst and a metal salt of the general formula (1): MXn [wherein, M is an alkali or alkaline earth metal ion; X is a perhalogen acid ion, perfluoroalkylsulfonic acid ion, bis(perfluoroalkylsulfonyl)amido ion or tris(perfluoroalkylsulfonyl)metaido ion; when M is an alkali metal ion, n is 1, while when M is an alkaline earth metal ion, n is 2].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 6-acyl-2-
The present invention relates to a method for producing a substituted naphthalene.

[0002]

2. Description of the Related Art 6-Acyl-2-substituted naphthalenes represented by 6-acetyl-2-methoxynaphthalene are useful compounds as pharmaceutical intermediates and the like.

[0003] As a method for producing such 6-acyl-2-substituted naphthalenes, for example, a method of reacting 2-methoxynaphthalene with acetyl chloride in nitrobenzene in the presence of aluminum chloride (Organic Synthete)
ses, 53 , 5 (1973)) A method of reacting 2-methoxynaphthalene with an acylating agent in a hydrofluoric acid solvent (Japanese Patent Application Laid-Open No. 61-178947). Boron trifluoride in a hydrofluoric acid solvent Reaction of 2-methylnaphthalene with an acylating agent in the presence of
No. 5756) In the presence of an indium chloride catalyst, 2
-Method of reacting methoxynaphthalene with an acylating agent (J. Chem. Soc. Perkin Trans.
1, 1703 (1994)).

[0004] However, this method requires attention to control of the reaction temperature, has a problem that the reaction time is long and the yield is low, and the method has a problem that hydrofluoric acid which is difficult to handle and has high toxicity is used. However, this method has a problem that the yield of the desired 2-methoxy-6-acylnaphthalene is low.

[0005]

SUMMARY OF THE INVENTION Under such circumstances,
The present inventors have conducted intensive studies on a method for selectively producing 6-acyl-2-substituted naphthalenes easily and with good yield without using a large amount of highly toxic reagents. The present inventors have found that 6-acyl-2-substituted naphthalenes can be selectively obtained at a high yield by using a specific metal salt such as lithium perchlorate in combination, and have led to the present invention.

[0006]

That is, the present invention provides 2-
A substituted naphthalene and an acylating agent are reacted with an acid catalyst and a compound of the general formula (1) (Wherein, M represents an alkali metal ion or an alkaline earth metal ion, and X represents a perhalate ion, a perfluoroalkylsulfonate ion, a bis (perfluoroalkylsulfonyl) amide ion or a tris (perfluoroalkylsulfonyl) methide ion.
When M is an alkali metal ion, n represents 1, and when M is an alkaline earth metal ion, n represents 2. The present invention provides a method for producing 6-acyl-2-substituted naphthalenes, wherein the reaction is carried out in the presence of a metal salt represented by the formula (1).

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. Examples of the substituent of the 2-substituted naphthalene include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group,
C 1-10 carbon atoms such as tert-butyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-decyl group
An alkenyl group having 2 to 10 carbon atoms such as a vinyl group, a propenyl group, a butenyl group, and a hexenyl group; for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, and an isobutoxy group , Sec-butoxy group, tert-butoxy group, n-
C1-C10 such as a hexyloxy group, a cyclohexyloxy group, an n-octyloxy group, and an n-decyloxy group
And the like.

[0008] Such 2-substituted naphthalenes include, for example, 2-methylnaphthalene, 2-ethylnaphthalene, 2-n
-Propyl naphthalene, 2-isopropyl naphthalene,
2-n-butylnaphthalene, 2-n-hexylnaphthalene, 2-cyclohexylnaphthalene, 2-n-decylnaphthalene, 2-vinylnaphthalene, 2-propenylnaphthalene, 2-butenylnaphthalene, 2-hexenylnaphthalene, 2-methoxy Naphthalene, 2-ethoxynaphthalene, 2-n-propoxynaphthalene, 2-tert-
Butoxynaphthalene, 2-n-octyloxynaphthalene and the like.

Examples of the acylating agent include carboxylic acid halides such as acetyl chloride, acetyl bromide, propionyl chloride, n-butyryl chloride, hexanoyl chloride, benzoyl chloride and benzoyl bromide, for example, acetic anhydride, propionic anhydride, Examples thereof include carboxylic anhydrides such as succinic acid and benzoic anhydride, and mixed acid anhydrides such as benzoyl triflate. Incidentally, acyl groups such as acetyl group, propionyl group and benzoyl group which constitute such an acylating agent are, for example, an alkoxy group having 1 to 10 carbon atoms, an aryl group which may be substituted, a hydroxy group, a carbon group having 1 carbon atom.
An alkylthio group having 10 to 10, an acyl group having 2 to 10 carbon atoms,
It may be substituted with an amino group protected with a protecting group.

Here, as the alkoxy group having 1 to 10 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group and a tert-butoxy group , N-
Hexyloxy group, cyclohexyloxy group, n-octyloxy group, n-decyloxy group and the like.Examples of the optionally substituted aryl group include, for example, phenyl group, naphthyl group and the like, and phenyl group, naphthyl group and the like. Is substituted with, for example, an alkyl group, an alkoxy group, a halogen atom, a nitro group, or the like.
-Methylphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 3-nitrophenyl group and the like.

Further, as the alkylthio group having 1 to 10 carbon atoms, an oxygen atom constituting the above alkoxy group having 1 to 10 carbon atoms is replaced with a sulfur atom, for example, a methylthio group,
Examples of the acyl group having 2 to 10 carbon atoms such as an ethylthio group include an acetyl group, a propionyl group, and a benzoyl group. Further, the protecting group for the amino group protected by the protecting group includes, for example, an acyl group such as an acetyl group and a trifluoroacetyl group, a trimethylsilyl group, and a tert group.
A trialkylsilyl group such as -butyldimethylsilyl group,
Examples thereof include a sulfonyl group such as a benzenesulfonyl group and a p-toluenesulfonyl group. Examples of the amino group protected by such a protecting group include an acetylamino group, a trimethylsilylamino group, and a benzenesulfonyloxyamino group.

The molar ratio of the 2-substituted naphthalenes to the acylating agent is not particularly limited, and may be appropriately determined in consideration of reactivity, economy and the like. The acylating agent may be used in an equimolar amount or more with respect to the 2-substituted naphthalenes.

As the acid catalyst, for example, aluminum chloride, aluminum bromide, indium chloride, antimony chloride (I
II), antimony (V) chloride, iron (II) chloride, iron (III) chloride, iron (III) bromide, metal chlorides such as titanium tetrachloride, titanium tetraisopropoxide, zirconium tetratert-butoxide, aluminum Metal alkoxides such as triisopropoxide, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, protonic acids such as phosphoric acid, bis (trifluoromethanesulfonyl) imide, bis (nonafluorobutanesulfonyl) imide, etc. Bis (perfluoroalkylsulfonyl) imides, tris (trifluoromethanesulfonyl) methane, tris (perfluoroalkylsulfonyl) methane such as tris (nonafluorobutanesulfonyl) methane, iodine, boron trifluoride, general formula (2) Wherein M ′ is a group IVa, group Va, group VIa, group VIIa, group VIII, group Ib, group IIb, group IIIb, group IVb, group Vb or group VIb When M 'is antimony, R represents a perfluoroalkyl group having 1 to 10 carbon atoms or an alkyl group having 1 to 10 carbon atoms, and A represents an oxygen atom, a nitrogen atom or a carbon atom. , N represents 3. Here, when A is an oxygen atom, m is 1; when A is a nitrogen atom, m is 2; when A is a carbon atom, m is 3; In the case of a metal atom other than antimony, R represents a trifluoromethyl group, A represents an oxygen atom, m represents 1, and n represents the valence of the metal atom.
When M ′ is a hydrogen atom, R is a hydroxy group and has 1 to 1 carbon atoms.
Represents a 10 perfluoroalkyl group, an alkyl group having 1 to 10 carbon atoms or an aryl group which may be substituted, A represents an oxygen atom, and m and n represent 1. And the like, and from the viewpoint of reaction activity, the compound represented by the general formula (2) is preferable.

Examples of the Group IVa metal atom include titanium,
Zirconium, hafnium and the like, Group Va metal atoms include, for example, vanadium, Group VIa metal atoms include, for example, molybdenum, and Group VIIa metal atoms include, for example, manganese.

The Group VIII metal atom is, for example, iron or the like; the Group Ib metal atom is, for example, copper or silver; the Group IIb metal atom is, for example, zinc or the like;
Examples of the group b metal atom include boron, aluminum,
Gallium, indium, etc., as Group IVb metal atoms, for example, tin, etc., as Group Vb metal atoms, for example, antimony, bismuth, etc., as Group VIb metal atoms, for example, tellurium, polonium, etc. .

Examples of the perfluoroalkyl group having 1 to 10 carbon atoms include a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a nonafluorobutyl group, an undecafluoropentyl group, a tridecafluorohexyl group and a heptadeca group. And a fluorooctyl group.

Examples of the alkyl group having 1 to 10 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group,
Examples include a tert-butyl group, an n-hexyl group, and an n-decyl group.

Examples of the optionally substituted aryl group include, for example, a phenyl group, a naphthyl group and the like, and an aromatic ring constituting such a phenyl group, a naphthyl group and the like, for example, an alkyl group, an alkoxy group, a halogen atom, a nitro group and the like. Are substituted, for example, a 2-methylphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, and a 3-nitrophenyl group.

Examples of the compound represented by the general formula (2) include hafnium triflate, iron (III) triflate, iron (II) triflate, boron triflate, aluminum triflate, gallium triflate, indium triflate, tin (II) triflate, Metal trifluoromethanesulfonate such as bismuth (III) triflate; antimony (II
I) Antimony (III) perfluoroalkyl sulfonates such as triflate, antimony (III) nonafluorobutanesulfonate, and antimony (III) bis (perfluoroalkylsulfonyl) such as antimony (III) bis (trifluoromethanesulfonyl) amide
Amides, antimony (III) antimony (III) such as tris (trifluoromethanesulfonyl) methide
Tris (perfluoroalkylsulfonyl) methides, for example, perfluoroalkylsulfonic acids such as trifluoromethanesulfonic acid and nonafluorobutanesulfonic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and sulfuric acid. .

[0020] The amount of the acid catalyst to be used is generally 0.01 to 500 mol%, preferably 0.1 to 30 mol%, based on the acylating agent.

[0021] The present invention relates to a compound represented by the general formula (1): (Wherein, M represents an alkali metal ion or an alkaline earth metal ion, and X represents a perhalate ion, a perfluoroalkylsulfonate ion, a bis (perfluoroalkylsulfonyl) amide ion or a tris (perfluoroalkylsulfonyl) methide ion.
When M is an alkali metal ion, n represents 1, and when M is an alkaline earth metal ion, n represents 2. It is important to use a metal salt represented by the formula (1), whereby 6-acyl-2-substituted naphthalenes can be selectively obtained.

In the formula of the metal salt represented by the above general formula (1),
Represents an alkali metal ion or an alkaline earth metal ion. Examples of the alkali metal ion include a lithium ion, a sodium ion, and a potassium ion. Examples of the alkaline earth metal ion include a calcium ion, a magnesium ion, and a barium ion. Ions and the like.

In the above formula (1), X represents a perhalogenate ion, a perfluoroalkyl sulfonate ion,
Represents a bis (perfluoroalkylsulfonyl) amide ion or a tris (perfluoroalkylsulfonyl) methide ion.

[0024] Examples of the perhalogenate ion include perchlorate ion, perbromate ion, periodate ion and the like. Examples of the perfluoroalkyl sulfonate ion include trifluoromethyl sulfonate ion, pentafluoroethyl sulfonate ion, heptafluoropropyl sulfonate ion, nonafluorobutyl sulfonate ion, and heptadecafluorooctyl sulfonate ion.

Examples of the bis (perfluoroalkylsulfonyl) amide ion include bis (trifluoromethylsulfonyl) amide ion, bis (pentafluoroethylsulfonyl) amide ion, bis (heptafluoropropylsulfonyl) amide ion, and bis (nonafluorobutyl) Sulfonyl) amide ion, bis (heptadecafluorooctylsulfonyl) amide ion and the like.

Examples of the tris (perfluoroalkylsulfonyl) methide ion include tris (trifluoromethylsulfonyl) methide ion, tris (pentafluoroethylsulfonyl) methide ion, tris (heptafluoropropylsulfonyl) methide ion, and tris (nonafluorobutylsulfonyl) methide ion.
And tris (heptadecafluorooctylsulfonyl) methide ion.

Examples of the metal salt represented by the general formula (1) include alkali metal perchlorates such as lithium perchlorate and sodium perchlorate, for example, lithium periodate,
Alkali metal periodates such as sodium periodate,
For example, alkaline earth metal perchlorates such as magnesium perchlorate, calcium perchlorate and barium perchlorate, for example, lithium trifluoromethanesulfonate, sodium trifluoromethanesulfonate, potassium trifluoromethanesulfonate, lithium nonafluorobutanesulfonate Alkaline earth metal perfluoroalkyl sulfonates such as alkali metal perfluoroalkyl sulfonates such as nato, lithium heptadecafluorooctanesulfonate, magnesium trifluoromethanesulfonate, calcium trifluoromethanesulfonate, and barium trifluoromethanesulfonate;
Alkali metal bis (perfluoroalkylsulfonyl) imide such as lithium bis (trifluoromethanesulfonyl) amide, sodium bis (trifluoromethanesulfonyl) amide, lithium bis (nonafluorobutanesulfonyl) amide, lithium tris (trifluoromethanesulfonyl) methide, sodium tris Alkali metal bis (perfluoroalkylsulfonyl) methane such as (trifluoromethanesulfonyl) methide and lithium tris (nonafluorobutanesulfonyl) methide; and alkali metal perchlorate and alkali metal bis (trifluoromethanesulfonyl) amide are preferable. .

The amount of the compound represented by the general formula (1) is usually 0.01 mol times or more, preferably 0.1 mol times or more with respect to the acylating agent since the effect is small if the amount is small. It is. There is no particular upper limit to the amount used, but if it is too large, it tends to be economically disadvantageous. Therefore, practically, it is 100 mol times or less, preferably 10 mol times or less, based on the acylating agent.
It is not more than molar times.

This reaction is usually carried out by mixing a 2-substituted naphthalene, an acylating agent, an acid catalyst and a metal salt represented by the general formula (1), and the mixing order is not particularly limited. This reaction may be performed in an atmosphere of an inert gas such as nitrogen gas or argon gas.

The reaction temperature is usually -50 to 200 ° C, preferably 0 to 150 ° C.

The reaction time is not particularly limited, and the progress of the reaction is analyzed by ordinary analytical means such as gas chromatography and high performance liquid chromatography, and the time when at least one of the 2-substituted naphthalenes or the acylating agent disappears is analyzed. The point at which the progress of the reaction is stopped may be determined as the end point.

[0032] This reaction may be carried out without a solvent or in the presence of a solvent. When the reaction is carried out in the presence of a solvent, the amount of the solvent used is not particularly limited. As the solvent, any solvent may be used as long as it is inert to the reaction.For example, dichloromethane, dichloroethane, chloroform, chlorobenzene, dichlorobenzene, halogenated hydrocarbon solvents such as benzotrifluoride, pentane, hexane, cyclohexane, heptane and the like Examples thereof include aliphatic hydrocarbon solvents, nitrated hydrocarbon solvents such as nitrobenzene, nitromethane, and nitroethane, and aprotic solvents such as acetonitrile and carbon disulfide, and more preferably, nitrated hydrocarbon solvents. These solvents may be used alone or as a mixture. Also use 2
When an aromatic hydrocarbon solvent such as benzene or toluene is more inert to the reaction than a substituted naphthalene, the aromatic hydrocarbon solvent may be used as the solvent.

After completion of the reaction, for example, the reaction mixture is subjected to extraction treatment by adding water or diluted alkaline water and, if necessary, an organic solvent insoluble in water, to obtain the desired 6-acyl-2-
An organic layer containing a substituted naphthalene is obtained, and the 6-acyl-2-substituted naphthalene can be taken out by concentrating the organic layer. 6-acyl taken out
The 2-substituted naphthalenes may be further purified by, for example, distillation, recrystallization, column chromatography and the like.

The 6-acyl-2-substituted naphthalenes include, for example, 6-acetyl-2-methoxynaphthalene,
6-propionyl-2-methoxynaphthalene, 6-butyryl-2-methoxynaphthalene, 6-isobutyryl-2
-Methoxynaphthalene, 6-valeryl-2-methoxynaphthalene, 6-pivaloyl-2-methoxynaphthalene,
6-benzoyl-2-methoxynaphthalene, 6-acetyl-2-ethoxynaphthalene, 6-propionyl-2-
Ethoxynaphthalene, 6-pivaloyl-2-ethoxynaphthalene, 6-benzoyl-2-ethoxynaphthalene,
6-acetyl-2-butoxynaphthalene, 6-propionyl-2-butoxynaphthalene,

6-acetyl-2-methylnaphthalene, 6-propionyl-2-methylnaphthalene, 6-butyryl-2
-Methylnaphthalene, 6-isobutyryl-2-methylnaphthalene, 6-valeryl-2-methylnaphthalene, 6-
Pivaloyl-2-methylnaphthalene, 6-benzoyl-
2-methylnaphthalene, 6-acetyl-2-ethylnaphthalene, 6-propionyl-2-ethylnaphthalene, 6
-Pivaloyl-2-ethylnaphthalene, 6-benzoyl-2-ethylnaphthalene, 6-acetyl-2-butylnaphthalene, 6-propionyl-2-butylnaphthalene,
6-acetyl-2-vinylnaphthalene, 6-propionyl-2-vinylnaphthalene, 6-pivaloyl-2-vinylnaphthalene, 6-benzoyl-2-vinylnaphthalene, 6-acetyl-2-butenylnaphthalene, 6-propionyl- 2-butenylnaphthalene and the like can be mentioned.

[0036]

According to the present invention, 6-acyl-2 is obtained by reacting a 2-substituted naphthalene with an acylating agent in the presence of an acid catalyst and a specific metal salt such as lithium perchlorate. -Substituted naphthalenes can be obtained selectively and in good yield.

[0037]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 A reaction vessel was charged with 141 mg of 2-methoxynaphthalene, 91 mg of acetic anhydride, 0.57 g of lithium perchlorate and 0.9 ml of nitromethane in an argon atmosphere at room temperature, and further 25 mg of antimony (III) triflate.
Was added and the mixture was stirred and maintained at an internal temperature of 50 ° C. for 4 hours. After cooling the obtained reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with diethyl ether. After the obtained oil layer was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the filtrate was analyzed by gas chromatography. As a result, 6-acetyl-2-methoxynaphthalene was produced in a 93% yield. . By-products include 1-acetyl-2-methoxynaphthalene, 8-acetyl-2-methoxynaphthalene and diacetyl-2-
Methoxy naphthalene was produced. 6-acetyl-2
The ratio (position selectivity) of 6-acetyl-2-methoxynaphthalene to the acetylated product of -methoxynaphthalene and the by-product was 95%.

Examples 2 to 11 In the same manner as in Example 1, except that the catalyst shown in Table 1 below was used in place of antimony (III) triflate, the same molar ratio as in Example 1 was used. Methoxy naphthalene was obtained. The results are shown in Table 1. The regioselectivity in Table 1 represents the ratio of 6-acetyl-2-methoxynaphthalene to the acetylated product.

[0040]

[Table 1]

Examples 12 to 13 The same operation as in Example 1 was carried out except that the compounds shown in Table 2 were used in place of lithium perchlorate, to give 6-acetyl-2-methoxynaphthalene. I got
The results are shown in Table 2. The regioselectivity in Table 2 represents the ratio of 6-acetyl-2-methoxynaphthalene to the acetylated product.

[0042]

[Table 2]

Example 14 The reaction was carried out in the same molar ratio as in Example 1 except that isobutanoic anhydride was used in place of acetic anhydride, and 6-isobutanoyl-2-methoxynaphthalene was obtained in a yield of 65. %. The starting material 2-methoxynaphthalene is 21
%, But no other by-produced isobutanoyl compound was found on the gas chromatogram.

Comparative Example 1 The procedure of Example 1 was repeated, except that lithium perchlorate was not added.
-Methoxynaphthalene was obtained in a yield of 8%. The ratio of 6-acetyl-2-methoxynaphthalene to the resulting acetylated product (position selectivity) was 20%.

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Claims (3)

[Claims] Claims 1. A 2-substituted naphthalene and an acylating agent are reacted with an acid catalyst and a compound of the general formula (1) (Wherein, M represents an alkali metal ion or an alkaline earth metal ion, and X represents a perhalate ion, a perfluoroalkylsulfonate ion, a bis (perfluoroalkylsulfonyl) amide ion or a tris (perfluoroalkylsulfonyl) methide ion.
When M is an alkali metal ion, n represents 1, and when M is an alkaline earth metal ion, n represents 2. A) producing a 6-acyl-2-substituted naphthalene. 2. An acid catalyst represented by the general formula (2): Wherein M ′ is a group IVa, group Va, group VIa, group VIIa, group VIII, group Ib, group IIb, group IIIb, group IVb, group Vb or group VIb When M 'is antimony, R represents a perfluoroalkyl group having 1 to 10 carbon atoms or an alkyl group having 1 to 10 carbon atoms, and A represents an oxygen atom, a nitrogen atom or a carbon atom. , N represents 3. Here, when A is an oxygen atom, m is 1; when A is a nitrogen atom, m is 2; when A is a carbon atom, m is 3; In the case of a metal atom other than antimony, R represents a trifluoromethyl group, A represents an oxygen atom, m represents 1, and n represents the valence of the metal atom.
When M ′ is a hydrogen atom, R is a hydroxy group and has 1 to 1 carbon atoms.
Represents a 10 perfluoroalkyl group, an alkyl group having 1 to 10 carbon atoms or an aryl group which may be substituted, A represents an oxygen atom, and m and n represent 1. The method for producing a 6-acyl-2-substituted naphthalene according to claim 1, which is a compound represented by the formula: 3. The method according to claim 2, wherein the metal salt represented by the general formula (2) is an alkali metal perchlorate or an alkali metal bis (trifluoromethanesulfonyl) amide.
A method for producing an acyl-2-substituted naphthalene.