JP2010077089A - Method for producing halopyrazinecarboxamide compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for halogenating a pyrazinecarboxamide derivative that does not require the use of an environmentally problematic solvent, does not generate harmful gases and the like and can be practiced safely, simply and economically on an industrial scale. <P>SOLUTION: The method for producing a halopyrazinecarboxamide compound represented by general formula (3) [wherein R is a hydrogen atom, an acyl group, a carbamoylalkyl group or a carboxyalkyl group; and X is a halogen atom] comprises causing pyrazinecarboxamide to react with a quaternary ammonium tribromide such as tetra-n-butylammonium tribromide, benzyltriethylammonium tribromide or the like in the presence of a base such as 2,6-lutidine or the like in a DMF solution. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a halopyrazinecarboxamide compound. The halopyrazinecarboxamide compound is useful, for example, as an antiviral agent or a synthetic intermediate thereof.

  It is known that the halopyrazinecarboxamide compound is useful as an antiviral agent (Patent Document 1).

  In Patent Document 1, a halopyrazinecarboxamide derivative is said to be available by purchasing a commercially available product, a known production method or a method according thereto, and a combination thereof. The production method is described in, for example, J.A. Am. Chem. Soc. . 71, 78 (1949), J. MoI. Am. Chem. Soc. 78, 242-244 (1956), J. Am. Heterocycl. Chem. 15 (4), 665-670 (1978), J. MoI. Chem. Soc. 1379 (1955), US Pat. No. 5,597,823, and the like. In order to obtain the target halopyrazinecarboxamide derivative, multi-step synthesis via a plurality of functional group transformations is necessary, and it is difficult to say that it is a simple method in practice.

  In a method using a single halogen such as chlorine or bromine as a halogenating agent, a halogen-based solvent such as methylene chloride is inactive to these halogenating agents and has been widely used. However, in recent years, the adverse effects on the environment of organic halides, particularly organic chlorine compounds, have become a problem, and it is well known that clean chemical reactions that do not use environmentally harmful compounds are required. Further, the use of sulfuryl halides such as sulfuryl chloride has an essential drawback that it generates harmful sulfur dioxide, and there is a problem of avoiding the use from the viewpoint of environmental protection.

Japanese Patent No. 3453362

  Therefore, the present invention solves the above problems, does not use environmentally problematic solvents, does not generate harmful gases, etc., and can be implemented safely, simply and economically on an industrial scale. It is an object of the present invention to provide a method for halogenating pyrazinecarboxamide derivatives.

As a result of diligent research on the halogenation method of pyrazinecarboxamide derivatives in view of the above circumstances, the present inventors have found that the above-described problems can be solved by the following novel means, and have completed the present invention. .
The object of the present invention has been achieved by the following means.
1) The following general formula (1)

[Wherein R represents a hydrogen atom, an acyl group, or an optionally substituted carbamoylalkyl or carboxyalkyl group. ]
A pyrazinecarboxamide compound represented by the following general formula (2)

[Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents an alkyl group, an aralkyl group or an aryl group. X represents a chlorine atom or a bromine atom. ]
A compound represented by the following general formula (3):

[Wherein R represents a hydrogen atom, an acyl group, or an optionally substituted carbamoylalkyl or carboxyalkyl group. X represents a halogen atom. ]
The manufacturing method of the halopyrazinecarboxamide compound represented by these.
2) The following general formula (4)

[Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents an alkyl group, an aralkyl group or an aryl group. X represents a chlorine atom or a bromine atom. ]
Elemental halogen compound after reacting represented in compound represented by the X _2, represented by the general formula which comprises reacting a pyrazine carboxamide compound represented by the general formula (1) (3) 1) The method for producing a halopyrazinecarboxamide compound according to 1).
3) The production method according to any one of 1) and 2), wherein a reaction solvent containing no halogen atom is used.
4) The method according to any one of 1) to 3), wherein the reaction is carried out in the presence of a base.
5) The method according to 4), wherein the base is a pyridine compound.

  According to the present invention, it is possible to halogenate a pyrazinecarboxamide compound on an industrial scale, safely, simply and economically without using a solvent having an environmental problem, without generating harmful gas, etc. The desired halopyrazinecarboxamide compound can be obtained with good yield.

  First, the pyrazinecarboxamide compound represented by the general formula (1) will be described.

  In the general formula (1), R preferably represents a hydrogen atom, an acyl group, or an optionally substituted carbamoylalkyl or carboxyalkyl group. Acyl groups include formyl groups, C2-C5 alkanoyl groups such as acetyl, propionyl, butyryl, isobutyryl and valeryl, and aroyl groups such as benzoyl and naphthoyl. Examples of the carbamoylalkyl group include a linear or branched C1-C6 alkyl group substituted with a carbamoyl group such as carbamoylmethyl, carbamoylethyl, carbamoylisopropyl and the like. Examples of the carboxyalkyl group include a linear or branched C1-C6 alkyl group substituted with a carboxyl group such as carboxymethyl, carboxyethyl, and carboxyisopropyl.

  Among the above-mentioned explanations, more preferable R includes a hydrogen atom, an acetyl group, a benzoyl group, a pivaloyl group, a carbamoylmethyl group, and a carboxymethyl group, and a hydrogen atom, an acetyl group, a benzoyl group, a pivaloyl group, and a carbamoylmethyl group are preferable. More preferred are a hydrogen atom, an acetyl group, and a carbamoylmethyl group. In the present invention, the most preferable R in the general formula (1) is a hydrogen atom.

  Next, the compound represented by the general formula (2) will be described.

In general formula (2), R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents an alkyl group, an aralkyl group or an aryl group. More specifically, R ¹ , R ² , R ³ and R ⁴ are alkyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms (for example, methyl group, ethyl group, n -Butyl group, etc.), aralkyl groups having 7 to 20 carbon atoms, preferably 7 to 15 carbon atoms, more preferably 7 to 10 carbon atoms (eg benzyl group, phenethyl group etc.), 6 to 20 carbon atoms, preferably 6 carbon atoms To 15 and more preferably 6 to 10 aryl groups (for example, phenyl group, naphthyl group, etc.). Among the above-described examples, preferable R ¹ , R ² , R ³ and R ⁴ are a benzyltriethylammonium group, a benzyltrimethylammonium group, and a tetra n-butylammonium group as an ammonium group.

  X represents a chlorine atom or a bromine atom.

  The halopyrazinecarboxamide compound represented by the general formula (3) will be described.

  In the general formula (3), R and X have the same meanings as described in the general formulas (1) and (2), and preferred ranges are also the same.

  Finally, the compound represented by formula (4) will be described.

In the general formula (4), R ¹ , R ² , R ^3, R ⁴ , and X are the same as those described in the general formula (2), and the preferred ranges are also the same.

  Although the typical example of a compound represented by General formula (1) used for this invention method is shown, this invention is not limited to these.

  Although the typical example of a compound represented by General formula (2) used for this invention method is shown, this invention is not limited to these.

  Representative examples of the compound represented by the general formula (3), which is the target compound of the method of the present invention, are shown below, but the present invention is not limited thereto. The compounds represented by the general formulas (1) and (3) have tautomers, but the chemical structural formulas described in this specification describe one of these tautomers for convenience. It should be understood that Needless to say, any tautomer is included in the scope of the present invention.

  Although the typical example of a compound represented by General formula (4) used for this invention method is shown, this invention is not limited to these.

  The production method of the present invention will be further described in detail. In the present invention, the amount of the compound represented by the general formula (2) is preferably in the range of 0.8 to 2.0 times moles relative to the pyrazinecarboxamide compound represented by the general formula (1), but more preferably. Is in the range of 0.85 to 1.8 times mol, particularly preferably 0.95 to 1.65 times mol. The whole amount of the compound represented by the general formula (2) may be used from the beginning, or for example, 0.2 moles may be divided into a plurality of times and used.

  In the step of reacting the pyrazinecarboxamide compound represented by the general formula (1) and the compound represented by the general formula (2), a solvent is used. Examples of the reaction solvent that can be used include ester solvents, aromatic hydrocarbon solvents, amide solvents, carboxylic acid solvents, alcohol solvents, water, and the like, which have been widely used in halogenation reactions. The reaction proceeds smoothly without using a halogen-based solvent such as methylene. These solvents may be used alone or in combination of two or more. Among the above-described explanations, ester solvents, aromatic hydrocarbon solvents, ketone solvents, amide solvents, carboxylic acid solvents, and water are preferable because of environmental conservation and less side reactions. Particularly preferred solvents are ethyl acetate, toluene, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, N, N′-dimethylimidazolidinone, propionic acid, acetic acid, water or these It is a combined system of 2 to 3 solvents selected from the inside.

  In the step of reacting the pyrazinecarboxamide compound represented by the general formula (1) and the compound represented by the general formula (2), there is no particular limitation on the order of addition of each raw material. In the production method of the present invention, when the compound represented by the general formula (2), which is a halogenating agent, is first charged into a reaction vessel and the pyrazinecarboxamide compound represented by the general formula (1) is reacted therewith, the general formula is not necessarily used. The compound represented by (2) does not need to be dissolved in a solvent, and a suspended state that can be stirred is sufficient. Conversely, even when the compound represented by the general formula (2) is added, in the case of powder addition, the solvent charged together with the pyrazinecarboxamide compound represented by the general formula (1) is sufficient in an amount capable of stirring. When the compound represented by the general formula (2) is dissolved in a solvent and reacted with the pyrazinecarboxamide compound represented by the general formula (1), an amide is used as a solvent for dissolving the compound represented by the general formula (2). It is preferable to use a system solvent. In the production method of the present invention, a pyrazinecarboxamide compound represented by the general formula (1) and a solvent are charged, and the compound represented by the general formula (2) is gradually added in a powder state or dissolved in a solvent. It is preferable to do this.

  In the production method of the present invention, after reacting a quaternary ammonium halide compound represented by the general formula (4) with a simple halogen compound, specifically bromine or chlorine, a pyrazinecarboxamide represented by the general formula (1) It is also possible to react the compounds, which is one preferred embodiment. In this case, it is preferable to use the same atom as the halide component of the quaternary ammonium halide compound, that is, chlorine when quaternary ammonium chloride is used, and bromine when quaternary ammonium bromide is used.

  That is, the quaternary ammonium halide compound represented by the general formula (4) is represented by 0.8 to 2.0 times mol of the pyrazinecarboxamide compound represented by the general formula (1), and the general formula (4). By reacting 0.85 to 1.15 moles of the halogen compound with respect to the quaternary ammonium halide compound, the compound represented by the general formula (1) is generated in the reaction system. By reacting the pyrazinecarboxamide compound represented by the general formula (1) here, the halopyrazinecarboxamide compound represented by the general formula (3) can be obtained. Solvents that can be used, bases that can be used, reaction conditions and preferred specific examples, preferred ranges, and the like are the steps in which the pyrazinecarboxamide compound represented by the general formula (1) is reacted with the compound represented by the general formula (2). Is identical to that of

  In the production method of the present invention, the reaction may be carried out in the presence of a base and is used in the present invention. Bases include primary or secondary organic bases (t-butylamine, 2,2,6,6-tetramethylpiperazine, etc.), tertiary organic bases (triethylamine, tri-n-propylamine, tri-n-butylamine) , N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5 Nonene, 1,4-diazabicyclo [2.2.2] octane, etc.), pyridines (pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,6-lutidine, etc.), alkali metal alkoxides ( Sodium methoxide, sodium ethoxide, sodium t-butoxide, etc.), alkali metal hydroxide (sodium hydroxide, water) Potassium etc.), alkaline earth metal hydroxides (magnesium hydroxide), sodium acetate, potassium carbonate, sodium carbonate, and the like. Among these, pyridines are more preferable, and specific examples include pyridine, 2-methylpyridine, and 2,6-lutidine. The amount of the base to be used is preferably 0.1 to 3.0 times mol, more preferably 0.8 to 2.0 times mol for the pyrazinecarboxamide compound represented by the general formula (1).

  Although the reaction temperature in the manufacturing method of this invention is the range of -10-100 degreeC normally, Preferably it is 5-55 degreeC, More preferably, it is the range of 15-45 degreeC. While the reaction time varies depending on the amount charged, reaction temperature, concentration, etc., it is generally 3 hours to 72 hours, and more preferably 4 to 48 hours. The progress of the reaction can be followed by, for example, liquid chromatography, and optimal reaction conditions can be set. In the reaction step, an inert atmosphere is not particularly required, but the reaction may be performed in a nitrogen or argon stream.

  The process post-treatment in the production method of the present invention is performed by a general-purpose method employed in a normal organic synthesis reaction. Inactivation of excess halogenating agent is preferably treated with an aqueous sodium sulfite solution. After stopping the reaction, the reaction mixture is subjected to chemical engineering conventional means such as crystallization by adding a poor solvent, salting out, extraction, liquid-liquid separation, etc., if necessary, recrystallization, chromatography A halopyrazinecarboxamide compound represented by the general formula (3) can be obtained by purification using a technique such as the above.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.

Example 1: Synthesis of Compound (1b) Quaternary ammonium tribromide was synthesized according to the method described in the literature (Bull. Chem. Soc. Jpn., 1987, 60, 1159). To a solution of 18 g of compound (1) and 2,6-lutidine (16 mL) in DMF (100 mL), 53 g of tetra n-butylammonium tribromide was added in portions at 25 ° C. with stirring. After the reaction mixture was stirred at 25 ° C. for 24 hours, water (250 mL) was added. The precipitated crystals were collected by filtration, washed with water and dried to give 21.1 g of compound (1b) as brown crystals. Yield 81%.

Example 2: Synthesis of Compound (2b) To a solution of 24 g of Compound (1) and 2,6-lutidine (16 mL) in DMF (120 mL) was added 52 g of benzyltriethylammonium tribromide at 25 ° C. with stirring. After the reaction mixture was stirred at 25 ° C. for 18 hours, water (250 mL) was added. The precipitated crystals were collected by filtration, washed with water, washed with methanol, and dried to obtain 22.8 g of compound (2b) as tan crystals. Yield 71%.

Example 3 Synthesis of Compound (3b) To a solution of 13.9 g of Compound (3) and 2-picoline (10 mL) in DMF (30 mL) was added 53 g of tetra n-butylammonium tribromide at 25 ° C. with stirring. . The reaction mixture was stirred at 25 ° C. for 16 hours, and 10% brine (100 mL) was added. The precipitated crystals were collected by filtration, washed with water and dried to give 15.3 g of compound (3b) as brown crystals. Yield 70%.

Example 4: Synthesis of Compound (3c) Quaternary ammonium trichloride was synthesized according to the method described in the literature (J. Chem. Soc., 1923, 123, 654). To a solution of 13.9 g of compound (3) and 2,6-lutidine (16 mL), 39 g of tetra n-butylammonium trichloride was added dropwise at 25 ° C. over 60 minutes with stirring. The reaction mixture was stirred at 25 ° C. for 12 hours, and 20% brine (120 mL) was added dropwise. The precipitated crystals were collected by filtration, washed with water and dried to obtain 12.1 g of compound (3c) as pale yellow crystals. Yield 70%.

Example 5: Synthesis of compound (3b) 17 g of bromine was added to a suspension of 35 g of tetra n-butylammonium bromide in DMF (30 mL), acetic acid (10 mL) and water (3 mL) at 10 ° C, and the reaction mixture was allowed to warm to room temperature. Stir for 1 hour while warm. 2,6-lutidine (5 mL) and 13.9 g of compound (3) were added thereto in this order, and the reaction mixture was stirred at room temperature for 5 hours. Crystals precipitated by adding 10% brine (100 mL) were collected by filtration, washed with water, and dried to obtain 14.6 g of compound (3b) as brown crystals. Yield 67%.

Example 6: Synthesis of Compound (5b) To a solution of 19.6 g of Compound (5) and 2-picoline (9 mL) in DMF (50 mL) was added 53 g of tetra n-butylammonium tribromide at 25 ° C. with stirring. . To the reaction mixture, 20% brine (200 mL) stirred at 25 ° C. for 20 hours was added dropwise. The precipitated crystals were collected by filtration, washed with water and dried to obtain 14.9 g of compound (5b) as brown crystals. Yield 54%.

Example 7: Synthesis of Compound (6b) In a solution of 19.7 g of Compound (6) and 2-picoline (9 mL) in DMF (70 mL), 53 g of tetra n-butylammonium tribromide was stirred at 25 ° C. While adding in portions. The reaction mixture was added dropwise with 20% brine (200 mL) stirred at 25 ° C. for 28 hours. The precipitated crystals were collected by filtration, washed with water and dried to obtain 15.7 g of compound (6b) as brown crystals. Yield 57%.

Comparative Example 1: Synthesis of Compound (3b) Using Bromine 1 g of bromine was first added dropwise at 25 ° C. to a DMF (25 mL) solution of 13.9 g of Compound (3) and 2-picoline (9 mL). When the reaction mixture was heated to 50 ° C., the reaction started with a rapid exotherm to 65 ° C. because the bromine color did not disappear and the reaction did not start. A total of 18 g of bromine was slowly added dropwise, taking care that the reaction temperature did not exceed 65 ° C (exothermic). The reaction mixture was stirred at 60 ° C. for 3 hours, cooled to room temperature, and 10% brine (100 mL) was added. After the reaction mixture was stirred at room temperature for 2 hours, the precipitated crystals were collected by filtration, washed with water and dried to obtain 8.5 g of compound (3b) as dark brown crystals. However, from the HPLC analysis, the purity of (3b) was 80% (area%) or less, and a considerable amount of impurities was observed. Apparent yield 39%.

Comparative Example 2 Synthesis of Compound (3c) Using Sulfuryl Chloride 15 g of sulfuryl chloride was added to a solution of 13.9 g of DMAc (40 mL) of Compound (3) at room temperature, and the reaction mixture was heated to 65 ° C. and stirred for 6 hours. did. When analyzed by HPLC, the raw material (3) remained, but formation of the desired (3c) was not observed.

Claims (5)

The following general formula (1)

[Wherein R represents a hydrogen atom, an acyl group, or an optionally substituted carbamoylalkyl or carboxyalkyl group. ]
A pyrazinecarboxamide compound represented by the following general formula (2)

[Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents an alkyl group, an aralkyl group or an aryl group. X represents a chlorine atom or a bromine atom. ]
A compound represented by the following general formula (3):

[Wherein R represents a hydrogen atom, an acyl group, or an optionally substituted carbamoylalkyl or carboxyalkyl group. X represents a halogen atom. ]
The manufacturing method of the halopyrazinecarboxamide compound represented by these. The following general formula (4)

[Wherein R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents an alkyl group, an aralkyl group or an aryl group. X represents a chlorine atom or a bromine atom. ]
Elemental halogen compound after reacting represented in compound represented by the X _2, represented by the general formula which comprises reacting a pyrazine carboxamide compound represented by the general formula (1) (3) The method for producing a halopyrazinecarboxamide compound according to claim 1.   The production method according to claim 1, wherein a reaction solvent containing no halogen atom is used.   The method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a base.   The method according to claim 4, wherein the base is a pyridine-based compound.