JP2694453B2 - Method for producing pyrazine derivative - Google Patents

Description

[Detailed Description of the Invention] [Detailed Description of the Invention] The present invention relates to a method for producing a pyrazine derivative useful as a perfume ingredient.

[Prior Art] Pyrazine derivatives have the general formula The pyrazine derivative shown in (among others, R ₄ is a lower alkyl group and XR ₂ is a low carbon number alkoxy, alkylthio, dialkylamino group) is used as a food flavor because it significantly enhances the flavor of foods such as coffee and cocoa. In addition to being used, there are examples of use as a fragrance improving component of cosmetics.

Conventionally, these pyrazine derivatives are produced as follows.

The first method is represented by the general formula (I) (Wherein R ₁ represents hydrogen or an alkyl group and XR ₂ represents an alkoxy or alkylthio having a low carbon number), and the compound at the 2-position is an alkyl halide in the presence of sodium metal in liquid ammonia. A method of alkylating a group (US Pat. No. 3,767,425).

In addition, the second method uses L-leucine amide to
A method for obtaining isobutyl-3-methoxypyrazine (US Pat. No. 3,720,672).

[Problems to be Solved by the Invention] However, any of the above-described methods for producing a pyrazine derivative has a difficulty in production and is not suitable for industrially obtaining a desired pyrazine derivative.

The first method has a difficulty in treating a large amount of anmore used as a solvent and handling sodium metal.

That is, in the former case, the existing reaction device and the solvent recovery device cannot be used, a special device for ammonia recovery is required, and the equipment cost increases due to the installation of new equipment. Further, in the latter case, when excess metal sodium is used, it is not possible to perform an operation such as water injection immediately after solvent recovery when performing a post-treatment, and special care and ingenuity are required. Therefore, in the first method, generally, a method using equimolar amounts or less of metal sodium and an alkyl halide compound relative to the starting material is employed, and as a result, the reaction cannot be performed until the starting material is completely consumed.
The yield decreases. In addition, since the selectivity of the reaction is low in order to obtain a fragrance-grade product from the reaction product, a complicated refining operation is required, which is not an advantageous method in terms of manufacturing cost. have.

In the above first method, when a secondary halogenated alkyl compound such as isopropylpropromide or 2-octylbromide is used as the alkylating agent, the yield is lowered, and particularly 2-methyl-3-methylthio is used. In the reaction of pyrazine and isopropyl bromide, a more remarkable decrease in yield is observed.

In the second method, only a method for producing 2-isobutyl-3-methoxypyrazine among pyrazine derivatives is disclosed. When trying to produce other pyrazine derivatives, the starting main raw material must be changed, but the synthesis itself of the starting raw material is difficult and expensive.

In addition, this second method is one in which diazomethane is allowed to act on 2-hydroxy-3-isopropylpyrazine during the reaction, and should be applied to the production of other pyrazine derivatives such as ethoxy, methylthio and dimethylamino other than the above. However, it is difficult to carry out industrially.

In addition to the above-mentioned first and second methods, a method of reacting an alkyllithium used as an anion generator with a compound represented by the general formula (I) can be considered as in the case of sodium amide. However, in this case, not only the target compound in which the alkyl group of the alkylating agent (halogenated alkyl compound) is introduced into the 2-position methyl group of the compound (I) but the alkyl group of alkyllithium is the compound (I).
It is difficult to selectively and efficiently synthesize the desired pyrazine derivative with many by-products such as products exchanged with nuclear hydrogen at the 5th and 6th positions (and / or).

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a production method capable of producing a pyrazine derivative in a high yield and industrially advantageously.

[Means for Solving the Problems] The present invention provides a compound represented by the general formula (Wherein, R ₁ represents hydrogen or an alkyl group, and XR ₂ represents a low carbon number alkoxy, alkylthio or dialkylamino group), and the alkylating agent and a pyrazine represented by lithium diisopropylamide in an inert solvent. General formula characterized by reacting in the presence (Wherein R ₁ and XR ₂ represent the same as those described above, and R ₃ represents an alkyl group corresponding to the alkylating agent).

Examples of XR ₂ in the above formula include methoxy as an alkoxy group, ethoxy as an alkylthio group and methylthio as a dialkylamino group.

This reaction is appropriately determined depending on the types of the raw material pyrazines, the solvent, and the alkylating agent, but it may be carried out at a reaction temperature of -80 to 0 ° C, preferably -30 to -10 ° C.

Examples of the alkylating agent include C ₁ to C such as methyl iodide, ethyl bromide, isopropyl bromide, n-propyl bromide, and n-amyl bromide.
A C ₁₀ alkyl halide or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid is used.

Furthermore, as the above-mentioned inert solvent, for example, tetrahydrofuran, ether, or hexane is used.

[Operation] Since the present invention is configured as described above, the methyl group of the starting pyrazines is selectively alkylated, so that the desired pyrazine derivative can be produced with a small amount of by-products.

Further, since the present invention uses lithium diisopropylamide which is easier to handle than metallic sodium, alkyllithium, etc., it is possible to use an excess amount of lithium isopropylamide and alkyl halide with respect to the raw material pyrazines. The target pyrazine derivative can be produced in high yield by completely eliminating the raw materials. Also,
Lithium diisopropylamide can be subjected to post-treatment immediately after the completion of the reaction without performing any special operation by recovering the solvent.

EFFECTS OF THE INVENTION Since the present invention has the above-mentioned constitution, the pyrazine derivative can be produced in good yield and industrially advantageously.

That is, solvent recovery is easy, existing equipment can be utilized, and the treatment of lithium diisopropylamide is easy, and in addition to the primary halogenated alkyl compound, the secondary halogenated alkyl compound is used as the alkylating agent. Even in such a case, the target pyrazine derivative can be obtained in an extremely high yield by selectively alkylating the methyl group of the raw material pyrazines.

Further, it is possible to introduce two or more lithium diisopropylamides into the mesyl group of the raw material pyrazine at the same time by using a molar equivalent of lithium diisopropylamide in an amount equal to or more than 2 times the molar amount of the raw material pyrazine and an excess amount of the alkylating agent. It is also possible to introduce two different alkyl groups.

In addition, the reaction of the present invention produces almost no by-products that are difficult to separate, and the purity of 95% can be extremely easily obtained by one ordinary distillation operation.
The above pyrazine derivative can be obtained.

Further, according to the present invention, various pyrazine derivatives can be obtained from the same starting material only by changing the alkylating agent that is easily available.

EXAMPLES Hereinafter, examples of the present invention will be described, but the present invention is not limited thereto.

Example 1 A solution of 6.2 g (0.05 mol) of 2-methyl-3-methoxypyrazine in 50 ml of tetrahydrofuran was stirred in an atmosphere of an inert gas such as nitrogen or argon, while maintaining the liquid temperature at -30 to -20 ° C. To the solution, 30 ml of lithium diisopropylamine (0.05 mol equivalent amount) of a tetrahydrofuran / hexane solution was added dropwise over 15 minutes. After dropping, the mixture was further stirred for 30 minutes.
Then, while maintaining the liquid temperature at -25 to -15 ° C, 20 ml of tetrahydrofuran containing 12.3 g (0.1 mol) of isopropyl bromide.
The solution was added dropwise in 15 minutes. After the dropping, the liquid temperature was maintained at -15 to -10 ° C, and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure to recover tetrahydrofuran. 5 ml of water in the concentrated residue
Was added, and the mixture was extracted twice with 50 ml of ether. After drying the ether layer with anhydrous magnesium sulfate, anhydrous magnesium sulfate was filtered off, and ether was recovered from the filtrate. The concentrated residue was distilled under reduced pressure to obtain 6.23 g (yield 75%) of 2-isobutyl-3-methoxypyrazine having a boiling point of 105 to 107 ° C./mmHg.

Example 2 The procedure of Example 1 was repeated to obtain the products shown in the table below.

However, the product (R ₁ = -H, R ₂ = -CH (CH ₃ ) ₂ , XR ₂ =
-SCH ₃₎ For the reaction was carried out temperature and time at -30 ° C. and 6 hours.

Example 3 In an atmosphere of an inert gas such as nitrogen or argon 2-
A solution of 2.5 g (0.02 mol) of methyl-3-methoxypyrazine in 30 ml of tetrahydrofuran was stirred, and the liquid temperature was -30 to -20 ° C.
While maintaining the above, 29 ml (0.048 mol equivalent amount) of a lithium diisopropylamide solution was added dropwise to this solution in 15 minutes. After dropping, the mixture was further stirred for 1 hour. After that, increase the liquid temperature from -30 to -20.
A solution of 10.24 g (0.081 mol) of dimethyl sulfate in 10 ml of tetrahydrofuran was added dropwise over 15 minutes while maintaining the temperature at ℃. After dripping,
The liquid temperature was maintained at -25 to -20 ° C, and stirring was continued for 12 hours. The reaction solution was concentrated under reduced pressure to recover tetrahydrofuran. 10 ml was added to the concentrated residue, and the mixture was extracted twice with 50 ml of ether. After drying the ether layer with anhydrous magnesium sulfate,
The anhydrous magnesium sulfate was filtered off and ether was recovered from the filtrate. The concentrated residue is distilled under reduced pressure and the boiling point is 94-95 ℃ / 35mmH.
Thus, 1.99 g of 2-isopropyl-3-methoxypyrazine (yield: 65%) was obtained.

Example 4 A solution of 2.0 g (0.013 mol) of 2-n-propyl-3-methoxypyrazine obtained in Example 2 in 30 ml of tetrahydrofuran was stirred in an atmosphere of an inert gas such as nitrogen or argon, and the liquid temperature was adjusted to −. While maintaining the temperature at 30 to -20 ° C, 9.5 ml (0.016 mol equivalent amount) of a lithium diisopropylamide solution was added dropwise to this solution in 15 minutes. After dropping, the mixture was further stirred for 1 hour. Then, while maintaining the liquid temperature at −30 to −20 ° C., a solution of methyl iodide 3.3 g (0.023 mol) in tetrahydrofuran 5 ml was added.
Dropped in 15 minutes. After dropping, keep the liquid temperature at -25 to -20 ° C and
Further stirring was continued for an hour. The reaction solution was concentrated under reduced pressure to recover tetrahydrofuran. Add 5 ml of water to the concentrated residue,
It was extracted twice with 50 ml of ether. After drying the ether layer with anhydrous magnesium sulfate, anhydrous magnesium sulfate was filtered off, and ether was recovered from the filtrate. The concentrated residue was distilled under reduced pressure to obtain 1.53 g (yield 70%) of 2- (1-methylpropyl) -3-methoxypyrazine having a boiling point of 104-105 ° C / 30 mmHg.

All of the final products of the above-mentioned examples had a purity of 95% or more, and the yield was higher than that of the conventional production method.

In the conventional method (US Pat. No. 3,767,425), 2-isobutyl-3-methylthiopyrazine was obtained in a yield of 15% (based on the alkyl halide as a reference, and therefore, when it was determined based on the starting pyrazines as in the present invention. Is a lower yield), whereas the present invention provides a yield of 51% as described in Example 2. As described above, in the present invention, the intended pyrazine derivative can be obtained in a significantly high yield when the secondary alkyl halide compound is used as the alkylating agent.

In addition, all final products have boiling points and NMR (CDCl ₃ ),
It was confirmed by GS-MS that it was the desired pyrazine derivative.

Claims (4)

(57) [Claims] (1) General formula (Wherein, R ₁ represents hydrogen or an alkyl group, and XR ₂ represents a low carbon number alkoxy, alkylthio or dialkylamino group), and the alkylating agent and a pyrazine represented by lithium diisopropylamide in an inert solvent. General formula characterized by reacting in the presence (Wherein R ₁ and XR ₂ represent the same as those described above, and R ₃ represents an alkyl group corresponding to the alkylating agent). 2. The reaction temperature is -80 to 0 ° C. (1)
A method for producing a pyrazine derivative according to the item. 3. The method for producing a pyrazine derivative according to claim 1, wherein the alkylating agent is a C _{1 to} C ₁₀ alkyl halide or dialkyl sulfuric acid. 4. The method for producing a pyrazine derivative according to claim 1, wherein the inert solvent is tetrahydrofuran, ether, or hexane.