Method for producing pyrazine skeleton-containing compound and method of producing 2-aminopyridine skeleton-containing compound
The method addresses low yields and high costs in producing 2-aminopyridine skeleton-containing compounds by employing pyrazine skeleton-containing compounds in a multi-step reaction and chromatographic purification, achieving efficient and cost-effective production.
Patent Information
- Application Number
- JP2023122737
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2023-07-27
- Publication Date
- 2025-02-06
AI Technical Summary
Existing methods for producing 2-aminopyridine skeleton-containing compounds result in low yields and high manufacturing costs due to the use of expensive amination agents.
A method involving specific reaction and purification steps using pyrazine skeleton-containing compounds, including a reaction between first and second raw material compounds in the presence of a base, followed by a chromatographic purification without recrystallization, and subsequent reaction with a silylating agent and reducing agent to produce 2-aminopyridine skeleton-containing compounds.
The method achieves high yields and reduces production costs by utilizing pyrazine skeleton-containing compounds as efficient amination reagents, with yields of up to 63% for 2-aminopyridine skeleton-containing compounds.
Smart Images
Figure 2025018753000001_ABST
Abstract
Description
[Technical field]
[0001] The present invention relates to a method for producing a compound containing a pyrazine skeleton. The present invention also relates to a method for producing a compound containing a 2-aminopyridine skeleton, using the compound containing a pyrazine skeleton as an aminating agent. [Background technology]
[0002] The 2-aminopyridine skeleton plays an important role as a functional group that predicts the expression of drug efficacy. In fact, of the 32 small molecule therapeutic drugs approved by the FDA in 2019, 8 (25%) were compounds containing the 2-aminopyridine skeleton. Therefore, there is a need to develop an efficient manufacturing method for compounds containing the 2-aminopyridine skeleton.
[0003] For example, Non-Patent Document 1 proposes a method of using pyridine as a raw material and introducing an amino group to the 2-position with an aminating agent. In order to introduce an amino group to the 2-position of the pyridine skeleton as in Non-Patent Document 1, it is necessary to use an expensive aminating agent. [Prior art documents] [Non-patent literature]
[0004] [Non-Patent Document 1] J.Am.Chem.Soc.2020,142,8614~8618 Summary of the Invention [Problem to be solved by the invention]
[0005] However, in Non-Patent Document 1, the yield of the aminating agent is only 35%, which causes a problem of extremely high production costs.
[0006] Therefore, an object of the present invention is to provide a method for producing a pyrazine skeleton-containing compound which is useful as an amination reagent, and which has excellent yield and can reduce production costs. [Means for solving the problem]
[0007] As a result of intensive research into solving the above problems, the present inventors have found that the above problems can be solved by carrying out specific reaction steps and purification steps in a production method for a pyrazine skeleton-containing compound, and have thus completed the present invention.
[0008] That is, according to the present invention, the following inventions are provided. [1] The following formula (1): [ka] (In formula (1), R 1 and R 2 are each independently an electron-withdrawing group; R 3 and R 4 are each independently a halogen atom. A first raw material compound represented by the formula: The following formula (2): [ka] (In formula (2), R 5 indicates a protecting group. In the presence of a base, a second raw material compound represented by the formula: The following formula (3): [ka] (In formula (3), R 1 , R 2 , and R 3 is the same as in equation (1), and R 5 is the same as equation (2). A reaction step of synthesizing a pyrazine skeleton-containing compound represented by the following formula: a purification step of isolating the pyrazine skeleton-containing compound obtained in the reaction step by a chromatography method without a recrystallization operation; The method for producing a pyrazine skeleton-containing compound includes the steps of: [2] R 1 and R 2The electron-withdrawing groups are -CN, -NO2, -NR3 + , -SO3H, -CHO, -COOR, -COOH, and -COR, and R is an alkyl group having 1 to 6 carbon atoms. [3] R 5 is selected from the group consisting of a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, and an allyloxycarbonyl group. [4] The method for producing a pyrazine skeleton-containing compound according to any one of [1] to [3], wherein the base is at least one selected from the group consisting of triethylamine, pyridine, imidazole and N,N-diisopropylethylamine. [5] The method for producing a pyrazine skeleton-containing compound according to any one of [1] to [4], wherein the pyrazine skeleton-containing compound is an aminating agent. [6] The pyrazine skeleton-containing compound is represented by the following formula (3-1): [ka] (In formula (3-1), Boc represents a tert-butoxycarbonyl group.) The method for producing the pyrazine skeleton-containing compound according to any one of [1] to [5], [7] Formula (4): [ka] (In formula (4), R 6 represents a linear or cyclic hydrocarbon group which may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom and a halogen atom, n is an integer of 0 to 4, provided that when n is 0, the hydrogen atom of the pyridine ring is not substituted, and when n is 2 or more, two of the R 6 may be bonded to each other to form a ring structure.) A third raw material compound represented by the formula: by reacting a pyrazine skeleton-containing compound produced by the method according to any one of [1] to [6] in the presence of a silylating agent and a reducing agent, The following formula (5): [ka] (In formula (5), R 5 is the same as equation (3), and R 6 and n are the same as in formula (4). The present invention relates to a method for producing a compound having a 2-aminopyridine skeleton, the method comprising the step of synthesizing a compound having a 2-aminopyridine skeleton represented by the following formula: [8] The method for producing a 2-aminopyridine skeleton-containing compound according to [7], wherein the silylating agent is at least one selected from the group consisting of t-butyldimethylsilyl chloride and N,O-bis(trimethylsilyl)acetamide. [9] The method for producing a 2-aminopyridine skeleton-containing compound according to [7] or [8], wherein the reducing agent is zinc.
[10] The method for producing a 2-aminopyridine skeleton-containing compound according to any one of [7] to [9], further comprising a purification step of separating and isolating the 2-aminopyridine skeleton-containing compound obtained in the reaction step by a chromatographic method. Effect of the Invention
[0009] According to the present invention, it is possible to provide a pyrazine skeleton-containing compound that is useful as an amination reagent, which has excellent yield and can reduce production costs. Also, according to the present invention, it is possible to provide a method for producing a 2-aminopyridine skeleton-containing compound using the pyrazine skeleton-containing compound, which has excellent yield and can reduce production costs. [Brief description of the drawings]
[0010] [Figure 1] 1 is a 1H-NMR spectrum of the pyrazine skeleton-containing compound synthesized in Example 1. [Diagram 2]1 is a 13C-NMR spectrum of the pyrazine skeleton-containing compound synthesized in Example 1. [Diagram 3] 1 is a 1H-NMR spectrum of the 2-aminopyridine skeleton-containing compound synthesized in Example 1. [Figure 4] 1 is a 13C-NMR spectrum of the 2-aminopyridine skeleton-containing compound synthesized in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0011] [Method of producing a compound containing a pyrazine skeleton] <Reaction process> The method for producing a pyrazine skeleton-containing compound according to the present invention includes a reaction step of reacting a first raw material compound described below with a second raw material compound described below in the presence of a base to synthesize a pyrazine skeleton-containing compound described below.
[0012] (First raw material compound) The first raw material compound used in the present invention is represented by the following formula (1): [ka] (In formula (1), R 1 and R 2 are each independently an electron-withdrawing group; R 3 and R 4 are each independently a halogen atom. It is expressed as: In the above formula (1), R 1 and R 2 The electron-withdrawing group may be any known electron-withdrawing group, and is not particularly limited. Examples of the electron-withdrawing group include -CN, -NO2, -NR3 + , -SO3H, -CHO, -COOR, -COOH, and -COR, where R is an alkyl group having 1 to 6 carbon atoms. Among these electron-withdrawing groups, -CN is preferable. R 3 and R 4The halogen atom includes a chlorine atom, a bromine atom, and a fluorine atom, preferably a chlorine atom and a bromine atom, and more preferably a chlorine atom.
[0013] Preferred embodiments of the first raw material compound include, for example, the following compounds: The first raw material compound may be used alone or in combination of two or more kinds. [ka] JPEG2025018753000010.jpg46147
[0014] (Second raw material compound) The second raw material compound used in the present invention is represented by the following formula (2): [ka] (In formula (2), R 5 indicates a protecting group. It is expressed as: In the above formula (2), R 5 The protecting group of R may be any known protecting group for an amino group, and is not particularly limited. 5 Examples of the protecting group include a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), and an allyloxycarbonyl group (Troc), etc. Among these protecting groups, a tert-butoxycarbonyl group (Boc) is preferred.
[0015] Preferred embodiments of the second raw material compound include, for example, the following compounds: The second raw material compound may be used alone or in combination of two or more kinds. [ka]
[0016] (base) Examples of the base used in the present invention include triethylamine, pyridine, imidazole, and N,N-diisopropylethylamine. Among these bases, triethylamine is preferred. The base may be used alone or in combination of two or more. The amount of base added can be appropriately adjusted depending on the types of raw materials and reaction conditions.
[0017] (solvent) The synthesis reaction of the pyrazine skeleton-containing compound may be carried out in the presence of a solvent. The solvent is not particularly limited, and a conventional organic solvent can be used. As the organic solvent, for example, aromatic hydrocarbon solvents such as benzene, toluene, o-, m-, p-xylene, mesitylene, etc.; aliphatic hydrocarbon solvents such as hexane and cyclohexane, etc.; halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, o-dichlorobenzene, etc.; ether-based solvents such as tetrahydrofuran, dioxane, diethyl ether, glyme, diglyme, etc.; fluorine-containing organic solvents such as hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, dichloropentafluoropropane, etc. can be used. Among these, benzene, toluene, o-, m-, and p-xylene, mesitylene, dichloromethane, chloroform, chlorobenzene, o-dichlorobenzene, diethyl ether, dioxane, THF (tetrahydrofuran), hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and the like, and mixtures thereof are preferred.
[0018] (Reaction conditions) In the synthesis reaction of a pyrazine skeleton-containing compound, the molar ratio of the first raw material compound to the second raw material compound is preferably 1:0.8 to 1:1.5, more preferably 1:0.9 to 1:1.4, further preferably 1:1.0 to 1:1.3, and most preferably 1:1.05 to 1:1.2. By adjusting the molar ratio of the first raw material compound to the second raw material compound, the reaction efficiency can be improved.
[0019] The synthesis reaction of the pyrazine skeleton-containing compound may be carried out under an inert gas (nitrogen; rare gases such as helium and argon, etc.) atmosphere. The reaction temperature is preferably from −80° C. to 30° C., more preferably from −40° C. to 10° C., even more preferably from −30° C. to 0° C., and even more preferably from −25° C. to −15° C. The reaction temperature may be changed stepwise. The reaction time is not particularly limited, but is preferably from 10 minutes to 4 hours, more preferably from 20 minutes to 2 hours, and even more preferably from 30 minutes to 1 hour.
[0020] (Compounds containing pyrazine skeleton) The pyrazine skeleton-containing compound obtained by the above reaction step has the following formula (3): [ka] (In formula (3), R 1 , R 2 , and R 3 is the same as in equation (1), and R 5 is the same as equation (2). It is expressed as R 1 , R 2 , and R 3 The preferred embodiment of is the same as that of formula (1), and R 5 The preferred embodiment of formula (2) is the same as that of formula (2).
[0021] Preferred embodiments of the pyrazine skeleton-containing compound include, for example, the following compounds. [ka] JPEG2025018753000015.jpg75165
[0022] Among the above pyrazine skeleton-containing compounds, the following compounds are preferred as an aminating agent in the synthesis reaction of a 2-aminopyridine skeleton-containing compound. [ka]
[0023] (Application) The pyrazine skeleton-containing compound obtained by the method for producing a pyrazine skeleton-containing compound of the present invention can be suitably used as an aminating agent. For example, it can be suitably used as an aminating agent in a synthesis reaction of a pyrazine skeleton-containing compound, particularly as an aminating agent in a synthesis reaction of a pyrazine skeleton-containing compound described in detail below.
[0024] <Purification process> The method for producing a pyrazine skeleton-containing compound of the present invention includes a purification step of separating and isolating the pyrazine skeleton-containing compound obtained in the above reaction step by a chromatographic method without a recrystallization operation. In particular, from the viewpoint of the isolation yield, it is preferable to isolate the pyrazine skeleton-containing compound by a chromatographic method (column chromatography) using a developing solution in which hexane and ethyl acetate are mixed in a ratio of 1:9 to 3:7.
[0025] The pyrazine skeleton-containing compound obtained in the above reaction step is not suitable for purification by a recrystallization operation utilizing the solubility difference between a poor solvent and a good solvent. This is because the solubility difference between the target pyrazine skeleton-containing compound and other impurities and by-products is small, making it difficult to select an appropriate poor solvent and good solvent. Therefore, in the present invention, by not performing a recrystallization operation in the purification step, it is possible to suppress a decrease in yield caused by a part of the target pyrazine skeleton-containing compound being dissolved in the poor solvent used for the recrystallization operation and being difficult to precipitate, which results in a decrease in yield.
[0026] The purification step may involve, in addition to chromatography, other procedures known in the art, such as reduced pressure filtration, solvent distillation, washing with a solvent, and ultrasonic washing.
[0027] [Method of producing a compound containing a 2-aminopyridine skeleton] <Reaction process> The method for producing a 2-aminopyridine skeleton-containing compound according to the present invention includes a reaction step of synthesizing the following 2-aminopyridine skeleton-containing compound by reacting the following third raw material compound with the above pyrazine skeleton-containing compound in the presence of a silylating agent and a reducing agent. Note that the pyrazine skeleton-containing compound is as described above, so a description thereof will be omitted here.
[0028] The above reaction process may be carried out stepwise. For example, the following third raw material compound and the above pyrazine skeleton-containing compound are reacted in the presence of a silylating agent to form an intermediate, and then the intermediate is reacted in the presence of a reducing agent to synthesize a 2-aminopyridine skeleton-containing compound. For example, the intermediate in reaction formula II of Example 2 shown below is assumed, but this is a guess based on a chemical reaction and does not limit the production method of the present invention in any way.
[0029] (Third raw material compound) The third raw material compound used in the present invention is represented by the following formula (4): [ka] (In formula (4), R 6 represents a linear or cyclic hydrocarbon group which may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom and a halogen atom, n is an integer of 0 to 4, provided that when n is 0, the hydrogen atom of the pyridine ring is not substituted, and when n is 2 or more, two of the R 6 may be bonded to each other to form a ring structure.) It is expressed as: In the above formula (4), R 6The number of carbon atoms in the hydrocarbon group is preferably 1 to 18, and more preferably 3 to 15. Examples of the hydrocarbon group include aliphatic hydrocarbon groups such as an alkyl group, alicyclic hydrocarbon groups such as a cycloalkyl group, and aromatic hydrocarbon groups such as a phenyl group. 6 may have two or more cyclic structures. Examples of the halogen atom include a fluorine atom, a bromine atom, and a chlorine atom. n is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, and further preferably an integer of 0 to 2.
[0030] Preferred embodiments of the third raw material compound include, for example, the following compounds: In this specification, Me in the chemical formulae represents a methyl group, and Ph represents a phenyl group. [ka] JPEG2025018753000019.jpg50142JPEG2025018753000020.jpg48128JPEG2025018753 000021.jpg22108JPEG2025018753000022.jpg30128JPEG2025018753000023.jpg6338
[0031] (Silylating Agent) The silylating agent used in the present invention is not particularly limited, and a conventionally known silylating agent can be used. Examples of the silylating agent include t-butyldimethylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, N,O-bis(trimethylsilyl)acetamide, triisopropylsilyl triflate, and N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide. Among these, it is preferable to use t-butyldimethylsilyl chloride and N,O-bis(trimethylsilyl)acetamide, and it is more preferable to use N,O-bis(trimethylsilyl)acetamide. The silylating agent may be used alone or in combination of two or more kinds. The amount of the silylating agent added can be appropriately adjusted depending on the type of raw material and the reaction conditions. The amount of the silylating agent added can be appropriately adjusted depending on the types of raw materials and reaction conditions.
[0032] (reducing agent) The reducing agent used in the present invention is not particularly limited, and a conventionally known reducing agent can be used. As the reducing agent, it is preferable to use zinc. Zinc may be activated or not, but it is preferable to activate it. The method of activating zinc is not particularly limited, but includes a method using acid, iodine, 1,2-dibromoethane, etc., or a method of preheating at 100°C or less, and preferably a method of preheating at 100°C or less. The amount of the reducing agent to be added can be appropriately adjusted depending on the types of raw materials and reaction conditions.
[0033] (solvent) The synthesis reaction of the 2-aminopyridine skeleton-containing compound may be carried out in the presence of a solvent. The solvent is not particularly limited, and a conventional organic solvent can be used. As the organic solvent, for example, aromatic hydrocarbon solvents such as benzene, toluene, o-, m-, p-xylene, mesitylene, etc.; aliphatic hydrocarbon solvents such as hexane and cyclohexane, etc.; halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, o-dichlorobenzene, etc.; ether-based solvents such as tetrahydrofuran, dioxane, diethyl ether, glyme, diglyme, etc.; fluorine-containing organic solvents such as hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, dichloropentafluoropropane, etc. can be used. Among these, benzene, toluene, o-, m-, and p-xylene, mesitylene, dichloromethane, chloroform, chlorobenzene, o-dichlorobenzene, diethyl ether, dioxane, THF (tetrahydrofuran), hexafluorobenzene, m-bis(trifluoromethyl)benzene, p-bis(trifluoromethyl)benzene, α,α,α-trifluoromethylbenzene, and the like, and mixtures thereof are preferred.
[0034] (Reaction conditions) In the synthesis reaction of the 2-aminopyridine skeleton-containing compound, the molar ratio of the third raw material compound to the pyrazine skeleton-containing compound is preferably 1:0.7 to 1:2.2, more preferably 1:1 to 1:1.9, even more preferably 1:1.2 to 1:1.7, and most preferably 1:1.4 to 1:1.6. By adjusting the molar ratio of the third raw material compound to the pyrazine skeleton-containing compound, the reaction efficiency can be improved.
[0035] The synthesis reaction of the 2-aminopyridine skeleton-containing compound may be carried out under an inert gas (nitrogen; rare gases such as helium and argon, etc.) atmosphere. The reaction temperature is preferably 0° C. or higher and 150° C. or lower, more preferably 20° C. or higher and 130° C. or lower, even more preferably 60° C. or higher and 100° C. or lower, and even more preferably 70° C. or higher and 90° C. or lower. The reaction temperature may be changed stepwise. When the reaction process is carried out stepwise as described above, the reaction may be carried out in the presence of a silylating agent at a temperature of 60° C. or higher and 100° C. or lower in the formation stage of an intermediate, and then in the presence of a reducing agent at a temperature of 0° C. or higher and 50° C. or lower in the synthesis stage of a 2-aminopyridine skeleton-containing compound. The reaction time is not particularly limited, but is preferably 0.5 hours to 8 hours, more preferably 1 hour to 5 hours, and further preferably 2 hours to 4 hours. When the reaction process is carried out stepwise as described above, the reaction may be carried out in the presence of a silylating agent in the formation of an intermediate for 0.5 hours to 4 hours, and then in the presence of a reducing agent in the synthesis of a 2-aminopyridine skeleton-containing compound for 0.5 hours to 4 hours.
[0036] (2-Aminopyridine skeleton-containing compounds) The 2-aminopyridine skeleton-containing compound obtained by the above reaction step has the following formula (5): [ka] (In formula (5), R 5 is the same as equation (3), and R 6 and n are the same as in formula (4). It is expressed as R 5 The preferred embodiment of is the same as that of formula (3), and R 6 and the preferred embodiments of n are the same as those in formula (4).
[0037] Preferred embodiments of the 2-aminopyridine skeleton-containing compound include, for example, the following compounds. [ka] JPEG2025018753000026.jpg56142JPEG2025018753000027.jpg44147JPEG2025018753 000028.jpg20127JPEG2025018753000029.jpg28130JPEG2025018753000030.jpg6343
[0038] <Purification process> The method for producing a 2-aminopyridine skeleton-containing compound of the present invention may further include a purification step of separating and isolating the 2-aminopyridine skeleton-containing compound obtained in the above reaction step by a chromatographic method. In particular, from the viewpoint of the isolation yield, it is preferable to isolate the pyrazine skeleton-containing compound by a chromatographic method (column chromatography) using a developing solution in which hexane and ethyl acetate are mixed in a ratio of 1:9 to 3:7.
[0039] The purification step may involve, in addition to chromatography, other procedures known in the art, such as reduced pressure filtration, solvent distillation, washing with a solvent, and ultrasonic washing. EXAMPLES
[0040] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.
[0041] <Analysis conditions> The structure of the pyrazine skeleton-containing compound obtained below is 1 H-NMR and 13 The compound was analyzed using C-NMR. ( 1 H-NMR conditions) NMR measurement equipment: AVANCE NEO spectrometer, Ascend 600 magnet (manufactured by BRUKER JAPAN) · 1 H-NMR measurement conditions: Frequency 600.03 MHz, CD2Cl2 solvent -Peaks detected for pyrazine-containing compounds (TMS internal standard): δ1.43 (s, 9H), 8.26 (s, 1H) ( 13C-NMR conditions) NMR measurement equipment: AVANCE NEO spectrometer, Ascend 600 magnet (manufactured by BRUKER JAPAN) · 13 C-NMR measurement conditions: Frequency 150.89 MHz, CD2Cl2 solvent -Peaks detected for pyrazine-containing compounds (TMS internal standard): δ27.7, 85.0, 111.9, 112.0, 126.5, 128.8, 140.8, 154.3, 157.5
[0042] The structure of the 2-aminopyridine skeleton-containing compound obtained below can be obtained under the following conditions. 1 H-NMR and 13 The compound was analyzed using C-NMR. ( 1 H-NMR conditions) NMR measurement equipment: AVANCE NEO spectrometer, Ascend 600 magnet (manufactured by BRUKER JAPAN) · 1 H-NMR measurement conditions: Frequency 600.03 MHz, CDCl3 solvent Detected peaks of 2-aminopyridine skeleton-containing compounds (TMS internal standard): δ1.55 (s, 9H), 6.94 (m, 1H), 7.66 (dd, J = 7.88, 8.59Hz, 1H), 7.97 (d, J = 8.59Hz, 2H), 8.33 (d, J = 4.68Hz, 1H) ( 13 C-NMR conditions) NMR measurement equipment: AVANCE NEO spectrometer, Ascend 600 magnet (manufactured by BRUKER JAPAN) · 13 C-NMR measurement conditions: Frequency 150.89 MHz, CDCl3 solvent Detected peaks of compounds containing 2-aminopyridine skeleton (TMS internal standard): δ28.5, 81.0, 112.6, 118.3, 138.4, 147.9, 152.7, 152.9
[0043] <Synthesis of compounds containing pyrazine skeleton> [Example 1] First, 2.000 g (1 equivalent) of 5,6-dichloro-2,3-dicyanopyrazine, 1.472 g (1.1 equivalents) of N-Boc-hydroxyamine, and 17.9 g of dehydrated THF were mixed uniformly in a reaction vessel at -20°C, and then 1.119 g (1.1 equivalents) of triethylamine was added at -20°C over 30 minutes, and the mixture was allowed to react for an additional 10 minutes to obtain a crude product (a compound containing a pyrazine skeleton) (reaction formula I below). [ka]
[0044] The obtained crude product was filtered to remove triethylamine hydrochloride, concentrated, and purified by preparative chromatography (a mixed solvent of hexane / ethyl acetate = 8 / 2 was used as the developing solvent, column: normal phase silica gel (Universal column L size (Yamazen Corp.), equipment: Smart Flash AKROS (Yamazen Corp.), temperature: room temperature, detection wavelength: 254 nm) to separate the desired pyrazine skeleton-containing compound. The yield of the pyrazine skeleton-containing compound was 54.3%. The purified pyrazine skeleton-containing compound was analyzed under the above analytical conditions. 1 H-NMR measurements and 13 C-NMR measurement was performed, as shown in Figure 1. 1 The H-NMR spectrum and Fig. 2 13 The C-NMR spectrum was obtained. As a result of the spectral analysis, it was confirmed that the compound was a pyrazine skeleton-containing compound of the above formula.
[0045] [Comparative Example 1] The target pyrazine skeleton-containing compound was separated in the same manner as in Example 1, except that a recrystallization operation using hexane was performed in the purification treatment of the crude product in Example 1. The yield of the pyrazine skeleton-containing compound was 34.6%. The reason for the decrease in yield due to the recrystallization operation is presumed to be that the target pyrazine skeleton-containing compound was partially dissolved in the poor solvent (hexane) used in the recrystallization operation, making it difficult to precipitate, and therefore the recrystallization efficiency was poor.
[0046] <Synthesis of compounds containing 2-aminopyridine skeleton> [Example 2] In a reaction vessel, 20 mg of pyridine (1 equivalent), 110 g (1.5 equivalents) of the pyrazine skeleton-containing compound (amination agent) synthesized in Example 1, 156 mg (3 equivalents) of N,O-bis(trimethylsilyl)acetamide (BSA, silylating agent), and 2 mL of dioxane were mixed and reacted at 80°C for 3 hours to obtain an intermediate. Next, 83 mg (5 equivalents) of zinc flakes (zero valence, reduction agent) preheated at 100°C or less and 2 mL of acetic acid were added, and the mixture was reacted at room temperature (25°C) for 3 hours to obtain a 2-aminopyridine skeleton-containing compound (reaction formula II below). Note that the intermediate in reaction formula II is a guess based on a chemical reaction, and does not limit the production method of the present invention in any way. [ka]
[0047] The obtained crude product was concentrated and purified by preparative chromatography (a mixed solvent of hexane / ethyl acetate = 8 / 2 was used as the developing solvent, column: normal phase silica gel (Universal Column M size (Yamazen Corp.), equipment: Smart Flash AKROS (Yamazen Corp.), temperature: room temperature, detection wavelength: 254 nm) to separate the target 2-aminopyridine skeleton-containing compound. The yield of the 2-aminopyridine skeleton-containing compound was 63%. The purified 2-aminopyridine skeleton-containing compound was purified under the above analytical conditions. 1 H-NMR measurements and 13 C-NMR measurements were performed, as shown in Figure 3. 1 The H-NMR spectrum and Fig. 4 13 The C-NMR spectrum was obtained. As a result of the spectral analysis, it was confirmed that the compound was a 2-aminopyridine skeleton-containing compound of the above formula.
Claims
1. The following formula (1): 【Chemistry 1】 (In formula (1), R １ and R ２ are each independently an electron-withdrawing group; R ３ and R ４ are each independently a halogen atom. A first raw material compound represented by the formula: The following formula (2): 【Chemistry 2】 (In formula (2), R ５ represents a protecting group.) In the presence of a base, a second raw material compound represented by the formula: The following formula (3): 【Chemistry 3】 (In formula (3), R １ , R ２ , and R ３ is the same as in formula (1), and R ５ is the same as formula (2). A reaction step of synthesizing a pyrazine skeleton-containing compound represented by the following formula: a purification step of isolating the pyrazine skeleton-containing compound obtained in the reaction step by a chromatography method without a recrystallization operation; The method for producing a pyrazine skeleton-containing compound includes the steps of:
2. The R １ and R ２ The electron-withdrawing group is -CN, -NO ２ , -NR ３ ＋ , -SO ３ 2. The method for producing a pyrazine skeleton-containing compound according to claim 1, wherein R is selected from the group consisting of H, -CHO, -COOR, -COOH, and -COR, and R is an alkyl group having 1 to 6 carbon atoms.
3. The R ５ is selected from the group consisting of a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, and an allyloxycarbonyl group.
4. The method for producing a pyrazine skeleton-containing compound according to claim 1, wherein the base is at least one selected from the group consisting of triethylamine, pyridine, imidazole and N,N-diisopropylethylamine.
5. The method for producing a pyrazine skeleton-containing compound according to claim 1 , wherein the pyrazine skeleton-containing compound is an aminating agent.
6. The pyrazine skeleton-containing compound is represented by the following formula (3-1): 【Chemistry 4】 (In formula (3-1), Boc represents a tert-butoxycarbonyl group.) The method for producing the pyrazine skeleton-containing compound according to any one of claims 1 to 5,
7. The following formula (4): 【Chemistry 5】 (In formula (4), R ６ represents a linear or cyclic hydrocarbon group which may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, a sulfur atom and a halogen atom, n is an integer of 0 to 4, provided that when n is 0, the hydrogen atom of the pyridine ring is not substituted, and when n is 2 or more, two of the R ６ may be bonded to each other to form a ring structure.) A third raw material compound represented by the formula: The method according to any one of claims 1 to 5, wherein the pyrazine skeleton-containing compound is reacted with a silylating agent and a reducing agent to form a pyrazine skeleton-containing compound. The following formula (5): 【Chemistry 6】 (In formula (5), R ５ is the same as in formula (3), and R ６ and n are the same as in formula (4). The present invention relates to a method for producing a 2-aminopyridine skeleton-containing compound, the method comprising the step of synthesizing a 2-aminopyridine skeleton-containing compound represented by the following formula:
8. The method for producing a 2-aminopyridine skeleton-containing compound according to claim 7, wherein the silylating agent is at least one selected from the group consisting of t-butyldimethylsilyl chloride and N,O-bis(trimethylsilyl)acetamide.
9. The method for producing a 2-aminopyridine skeleton-containing compound according to claim 7, wherein the reducing agent is zinc.
10. The method for producing a 2-aminopyridine skeleton-containing compound according to claim 7, further comprising a purification step of separating and isolating the 2-aminopyridine skeleton-containing compound obtained in the reaction step by a chromatographic method.