CN110621652A - Process for producing diaminobenzene compound - Google Patents
Process for producing diaminobenzene compound Download PDFInfo
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- CN110621652A CN110621652A CN201880031471.5A CN201880031471A CN110621652A CN 110621652 A CN110621652 A CN 110621652A CN 201880031471 A CN201880031471 A CN 201880031471A CN 110621652 A CN110621652 A CN 110621652A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
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Abstract
The purpose of the present invention is to provide a method for producing a diaminobenzene compound and a benzimidazole compound by a simple and inexpensive method. The present invention provides a method for producing a compound represented by the following formula (1) (wherein n is an integer of 1 to 4, and R is1Is alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, acyloxy group having 2 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, nitro group or halogen atom, when n is not less than 2, a plurality of R are1May be the same or different from each other, RAIs a hydrogen atom or a protecting group. ) The alkali metal salt of the aminonitrobenzene compound or the N-protected nitrobenzene compound and dithionous acidContacting the mixture to produce a compound represented by the following formula (2) (wherein R is1、RAAnd n is as defined in said formula (1). ) A method for producing a diaminobenzene compound or an N-protected aminobenzene compound, and a method for performing a deprotection reaction as required.
Description
Technical Field
The present invention relates to a novel method for producing a diaminobenzene compound useful as an intermediate for chemical products, raw drugs, and the like. Further, the present invention relates to a novel process for producing a benzimidazole derivative from a diaminobenzene compound obtained after producing the diaminobenzene compound by the production process.
Background
The benzimidazole derivative is used as an intermediate of chemical products, technical products and the like, and has very high utilization value. For example, the benzimidazole derivative represented by the following formula (5) has a very high industrial value as an intermediate of sartan prodrugs such as candesartan cilexetil (see, for example, patent documents 1 to 3).
(in the formula, R1An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acyloxy group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, a nitro group or a halogen atom,
R2is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. )
Generally, the benzimidazole derivative represented by the formula (5) is synthesized by the following method. First, the nitro group of the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the following formula (6) is reduced to synthesize a diaminobenzene compound or an N-protected aminobenzene compound represented by the following formula (7).
(in the formula, R1Is C1-C6 alkyl, C1An alkoxy group having 6 carbon atoms, an acyloxy group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, a nitro group or a halogen atom,
RAis a hydrogen atom or a protecting group. )
(in the formula, R1And RAThe same as defined in said formula (6). )
At this time, if it is RAA protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, formyl, acetyl, tosyl or nitrobenzenesulfonyl (hereinafter, this protecting group may be referred to as "R" in some casesA1") by deprotection to give the diaminobenzene compound.
Next, the resulting diaminobenzene compound is reacted with an orthoester derivative having a desired group, and condensation and cyclization reactions are performed to synthesize the benzimidazole derivative represented by the formula (5).
In the reduction of the nitro group of the aminonitrobenzene compound represented by the above formula (6), an expensive nickel catalyst (see patent document 1), a palladium catalyst (see patent document 2), or a highly toxic tin compound (see patent document 3) is used in the prior art.
In order to produce a drug substance such as candesartan cilexetil from a diaminobenzene compound and the benzimidazole derivative represented by the formula (5), a very large number of steps are required thereafter. It is therefore desirable that these intermediates be synthesized using reagents that are as inexpensive and easy to handle as possible. In the prior art, there is room for improvement in this point.
Documents of the prior art
Patent document
Patent document 1 International publication No. 2006/015134
Patent document 2 International publication No. 2015/173970
Patent document 3 International publication No. 2012/018325
Disclosure of Invention
Problems to be solved by the invention
The object of the invention is therefore: provided is a method for producing a diaminobenzene compound and a benzimidazole derivative more easily using a less expensive material.
Means for solving the problems
The present inventors have made extensive studies to solve the above-mentioned problems. As a result, they found that: even if the cheap dithionous acid ([ S ] is used2O2]2-) The reduction reaction of the aminonitrobenzene compound or the N-protected nitrobenzene compound of said formula (6) is also carried out. Further, they have found that the purity and yield of the diaminobenzene compound or the N-protected aminobenzene compound obtained can be improved by carrying out the reduction reaction in a reaction solvent containing an aprotic polar solvent (a reaction solvent which may contain water), or in the presence of an alkali metal carbonate, and have accomplished the present invention.
That is, (1) the first aspect of the present invention is: a process for producing a diaminobenzene compound or an N-protected aminobenzene compound represented by the following formula (2) by bringing an aminonitrobenzene compound or an N-protected nitrobenzene compound represented by the following formula (1) into contact with an alkali metal salt of dithionous acid.
(wherein n is an integer of 1 to 4,
R1is alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, acyloxy group having 2 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, nitro group or halogen atom, when n is not less than 2, a plurality of R are1May be the same as or different from each other,
RAis a hydrogen atom or a protecting group. )
(in the formula, R1、RAAnd n is as defined in said formula (1). )
Hereinafter, R in the above formula (1) may beAThe compound which is a hydrogen atom is simply referred to as "aminonitrobenzene compound". In addition, R in the formula (1) may beAThe compound when it is a protecting group is simply referred to as "N-protected nitrobenzene compound". In addition, when the "aminonitrobenzene compound" and the "N-protected nitrobenzene compound" are collectively referred to, they are sometimes simply referred to as "nitrobenzene compounds".
Similarly, R in the above formula (2) may beAThe compound which is a hydrogen atom is simply referred to as "diaminobenzene compound". In addition, R in the above formula (2) may beAThe compound when it is a protecting group is simply referred to as "N-protected aminobenzene compound". In addition, when "diaminobenzene compound" and "N-protected aminobenzene compound" are collectively referred to, they are sometimes simply referred to as "aminobenzene compound".
In the above formulae (1) and (2), R may be represented byAThe protecting group which is a tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylmethoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, formyl group, acetyl group, tosyl group, nitrobenzenesulfonyl group or the like is referred to as "RA1”。
(2) In the first aspect of the present invention, the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the formula (1) is preferably contacted with the alkali metal salt of dithionous acid in a reaction solvent containing an aprotic polar solvent.
(3) In the first aspect of the present invention, it is preferable that the reaction solvent contains water in an amount of 1 to 3 moles based on 1 mole of the alkali metal dithionite.
In the first aspect of the present invention, by satisfying the requirements (2) and (3), the decomposition of the alkali metal dithionite can be suppressed, the dissolution of the substrate and the reactant can be promoted, and the purity and the yield of the aminobenzene compound can be improved.
(4) In the first aspect of the present invention, the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the formula (1) is preferably contacted with the alkali metal salt of dithionous acid in the presence of an alkali metal carbonate. It is considered that the presence of the alkali metal carbonate suppresses side reactions such as sulfonation of the benzene ring. It is also considered that the alkali metal hydrogensulfate or sulfite produced in the reaction can be neutralized to accelerate the reaction. In addition, the extraction and separation of the aminobenzene compound can be facilitated.
(5) In the first aspect of the present invention, it is preferable that the alkali metal dithionite is used in an amount of 1 to 5 moles, based on 1 mole of the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the formula (1). By making the amount of the alkali metal dithionite used within the above range, the yield of the aminobenzene compound can be improved.
(6) In the first aspect of the present invention, it is preferable that in the formulae (1) and (2), R isAThe protecting group of (A) is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, formyl, acetyl, tosyl or nitrobenzenesulfonyl. In the case of these protecting groups, deprotection reaction thereof is easy to proceed.
(7) In the method (6), it is preferable that after the production of the N-protected aminobenzene compound, the resulting N-protected aminobenzene compound is brought into contact with an acid, a base or hydrogen to obtain a diaminobenzene compound.
(8) A second aspect of the invention is a method of: in the first aspect of the present invention, after the diaminobenzene compound is produced, the obtained diaminobenzene compound is reacted with an orthoester derivative represented by the following formula (3) (hereinafter, may be simply referred to as an "orthoester derivative") in the presence of an acid to produce a benzimidazole derivative represented by the following formula (4) (hereinafter, may be simply referred to as a "benzimidazole derivative").
(in the formula, R2An alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms,
R3the alkyl groups are C1-C6 alkyl groups, which may be the same or different. )
(in the formula, R1And n is as defined in said formula (1),
R2the same as defined in said formula (3). )
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, a diaminobenzene compound can be produced using an alkali metal dithionite salt which is less expensive and safer than the reducing agents used in the prior art. By using the alkali metal dithionite, the diaminobenzene compound can be easily separated and purified as compared with the method using a palladium catalyst in the prior art.
Further, by bringing the nitrobenzene compound into contact with the alkali metal dithionite in a reaction solvent containing an aprotic polar solvent, the decomposition of the alkali metal dithionite can be suppressed, the dissolution of the substrate and the reactant can be promoted, and the purity and yield of the aminobenzene compound can be improved. In this case, the reaction solvent may contain water, and the above-mentioned effects are remarkably exhibited by containing water.
In addition, by making alkali metal carbonate exist in the reaction system, the generation of by-products (polar impurities) in which benzene rings are sulfonated can be further suppressed. In addition, the purity and yield of the diaminobenzene compound obtained can be further improved by using a reaction solvent containing an aprotic polar solvent.
Further, by using the above-mentioned N-protected nitrobenzene compound, the formation of a by-product of sulfonation of a benzene ring (hereinafter, this by-product may be referred to as "polar impurity") can also be suppressed. The solubility of the obtained N-protected aminobenzene compound in a water-insoluble organic solvent is high. As a result, the high purity can be achieved more easily by the operations of water washing and extraction.
The benzimidazole derivative can be easily produced by reacting the diaminobenzene compound with an orthoester derivative. The obtained benzimidazole derivative can be used as an intermediate of various chemical products and raw drugs, so that the industrial utilization value of the benzimidazole derivative is very high.
Detailed Description
The present invention is a method for producing the aminobenzene compound by reducing the nitro group of the nitrobenzene compound to an amino group using an alkali metal dithionite. The nitrobenzene compound is mixed with an alkali metal dithionite for reduction. The following description will be made in order.
(raw Material Compound; Nitrobenzene Compound)
In the present invention, the nitrobenzene compound used as the raw material is a compound represented by the following formula (1).
In the formula (1), n is an integer of 1-4, preferably 1; r1An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acyloxy group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, a nitro group or a halogen atom; when n is greater than or equal to 2, a plurality of R1May be the same or different from each other. Among them, alkoxycarbonyl groups having 2 to 6 carbon atoms are preferable for use as intermediates of various substances and crude drugs. Further, R of the nitrobenzene compound1When the alkyl group has 1 to 6 carbon atoms and the alkoxycarbonyl group has 2 to 6 carbon atoms, the candesartan cilexetil can be used as a raw material of candesartan cilexetil. In addition, in the formula (1), n is preferably 1, and R is preferably used as an intermediate of sartan prodrugs1The alkyl group has 1 to 6 carbon atoms, and an alkoxycarbonyl group having 2 to 6 carbon atoms is particularly preferable for use as a raw material of candesartan cilexetil.
In addition, R1The position of (a) is not particularly limited. Among them, if used as a raw material of candesartan cilexetil, NHR is preferableAAdjacent carbon atoms of radical-bonded carbon atoms and R1And (4) bonding. Therefore, R is preferred1Bonded with the 1 st carbon atom to obtain 2-amino-3-nitroA phenyl compound or a 2-N-protected amino-3-nitrobenzene compound.
RAIs a hydrogen atom or a protecting group. RAIn the case of a hydrogen atom, the process (deprotection reaction) can be simplified.
In another aspect, RAIn the case of a protecting group, the obtained compound is the above-mentioned N-protected aminobenzene compound, and the purity can be easily improved by washing with water, extraction operation, or the like. Meanwhile, by having a protecting group, the production of a by-product (polar impurity) of benzene ring sulfonation can be suppressed. As specific examples of the protecting group, there can be cited: a protecting group (R) such as tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, formyl, acetyl, tosyl or nitrobenzenesulfonylA1). In the case of these protecting groups, deprotection reaction can be easily performed, and a diaminobenzene compound can be obtained. Among these specific protecting groups, R is preferred in view of the effect of inhibiting impurities and the ease of deprotection reactionA(RA1) Is tert-butoxycarbonyl.
The nitrobenzene compound can be produced by a known method.
(alkali Metal salt of dithionous acid)
In the present invention, the nitro group of the nitrobenzene compound is reduced to an amino group by an alkali metal dithionite. When the alkali metal dithionite is used, it is less expensive than the conventionally known palladium catalyst, and the obtained aminobenzene compound can be easily separated and purified. That is, after the reaction is completed, the alkali metal dithionite can be removed more easily than the palladium catalyst.
Among the alkali metal salts of dithionous acid, sodium and potassium are preferable as the alkali metal, and sodium is preferable from the viewpoint of availability and ease of handling. Specific examples of the alkali metal salt of dithionous acid include sodium dithionite and potassium dithionite, and sodium dithionite is preferable.
The alkali metal salt of dithionous acid may be a commercially available product. Some of the commercially available products contain sodium disulfite and potassium carbonate as impurities, and these products can be used in the present invention. The alkali metal salt of dithionous acid is not particularly limited, and a product having a purity of 70 to 100 mass% can be used. Among them, alkali metal salts of dithionous acid having a purity of 70 mass% or more and 95 mass% or less are industrially easily available and are also easily used in the present invention.
The amount of the alkali metal salt of dithionous acid used is not particularly limited. However, in order to allow the reduction reaction to proceed in a short period of time and to facilitate the post-treatment, the alkali metal dithionite is preferably used in an amount of 1 to 10 mol, more preferably 1 to 5 mol, and still more preferably 1 to 4 mol, based on 1 mol of the nitrobenzene compound.
In the present invention, the reduction reaction can be carried out only by allowing the alkali metal dithionite to be present in the reaction system. However, in order to smoothly progress the reaction in a short time and to suppress side reactions, it is preferable that an alkali metal carbonate is further present in the reaction system.
(alkali metal carbonate)
In the present invention, when an alkali metal carbonate is present in addition to the alkali metal dithionite in the reaction system, the reaction may be smoothly carried out in a short time while suppressing side reactions. Specifically, it is considered that the presence of the alkali metal carbonate can suppress side reactions such as sulfonation of the benzene ring. It is also considered that the alkali metal hydrogensulfate or sulfite produced in the reaction can be neutralized to promote the reaction. Further, since the dithionous acid is an inorganic salt, it is easily removed after the completion of the reaction, similarly to the alkali metal salt of dithionous acid. The alkali metal carbonate is not an essential component in the present invention, and can be reacted (reduced) even if not used. Particularly, when the N-protected nitrobenzene compound is used, the reaction proceeds well even without the use of an alkali metal carbonate.
In the reduction reaction using an alkali metal salt of dithionous acid, a base such as ammonia water is generally used for the neutralization reaction. In the present invention, although the reaction can be carried out using ammonia water, the reaction can be carried out smoothly and more quickly by using an alkali metal carbonate.
In the present invention, the alkali metal carbonate may be a known one. Specific examples thereof include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and rubidium carbonate. Among them, potassium carbonate and sodium carbonate are preferable in view of cost, reactivity, solubility and the like.
In the present invention, when an alkali metal carbonate is used, the amount thereof to be used is not particularly limited. The amount of the alkali metal carbonate used is preferably 0.5 to 5 mol, more preferably 1.0 to 3.0 mol, based on 1 mol of the nitrobenzene compound, in order to obtain the desired product in high yield.
(reaction conditions in reduction)
(reaction solvent)
In the present invention, the nitrobenzene compound is reduced with the alkali metal dithionite, as long as both are in sufficient contact. Therefore, it is preferable that the nitrobenzene compound and the alkali metal dithionite are stirred and mixed in the reaction solvent to be brought into sufficient contact with each other.
In the present invention, the reaction solvent used is not particularly limited as long as it does not adversely affect the nitrobenzene compound and the alkali metal dithionite and allows the reduction reaction to proceed smoothly. Among them, in consideration of the solubility of the nitrobenzene compound, the alkali metal dithionite, the alkali metal carbonate used as needed, and the resulting aminobenzene compound, there are:
water;
an alcohol;
aprotic polar solvents such as acetone, acetonitrile, Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP);
aromatic solvents such as toluene;
halogen-based solvents such as methylene chloride.
These solvents can also be used in the form of a mixed solvent.
Among them, in order to improve the purity and yield of the obtained aminobenzene compound, it is preferable to use a reaction solvent containing an aprotic polar solvent such as DMF, DMA, DMSO, NMP, or the like. From the viewpoint of yield and purity, DMF is particularly preferably used.
In the present invention, the reaction solvent preferably contains water. The amount of water contained in the reaction solvent is not particularly limited. Among them, the amount of water is preferably 1 to 3 moles based on 1 mole of the alkali metal salt of dithionous acid in order to improve the solubility of the alkali metal salt of dithionous acid and suppress the side production of the polar impurities.
Preferred examples of the reaction solvent used in the present invention include a mixed solvent containing an aprotic polar solvent such as DMF, DMA, DMSO, or NMP and water. Particularly, a mixed solvent containing DMF and water is preferably used. Even when the mixed solvent is used, the amount of water is preferably 1 to 3 moles based on 1 mole of the alkali metal dithionite. When the reaction solvent contains an aprotic polar solvent such as DMF, the formation of impurities (presumably by-products (polar impurities)) substituted with sulfo groups generated from the alkali metal salt of dithionous acid can be suppressed. In addition, when the reaction solvent contains water, the amount of the alkali metal dithionite dissolved can be increased. However, when the amount of water in the reaction solvent is too large, for example, when the amount of water exceeds 3 moles based on 1 mole of the alkali metal dithionite, the amount of the polar impurities produced tends to increase.
When a mixed solvent is used as the reaction solvent, an aromatic solvent such as toluene may be added to the mixed solvent of water and the aprotic polar solvent. When the aromatic solvent is contained, the amount of the nitrobenzene compound as the raw material and the amount of the aminobenzene compound as the product dissolved can be increased, and therefore, the stirring efficiency can be improved. In this case, the mixing ratio of the mixed solvent is: the amount of the aprotic polar solvent is preferably 1 to 100ml and the amount of the aromatic solvent is preferably 1 to 100ml, more preferably 2 to 25ml and the amount of the aromatic solvent is preferably 2 to 25ml, based on 1g of the nitrobenzene compound. However, in this case, since the amount of the impurities tends to increase when the amount of water is large in the reaction solvent, the amount of water is preferably 1 to 3 moles based on 1 mole of the alkali metal dithionite.
In the present invention, when the reaction solvent is used, it is preferable to use an amount that allows sufficient mixing of the components. Specifically, the reaction solvent is preferably used in an amount of 1 to 250ml, more preferably 2 to 80ml, and still more preferably 2 to 25ml, based on 1g of the nitrobenzene compound at a temperature of 23 ℃. When a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent may satisfy the above range.
(method of introducing into reaction System)
In the present invention, a method for introducing the nitrobenzene compound, the alkali metal dithionite and, if necessary, the alkali metal carbonate into a reaction system (a place where a reaction proceeds, such as in a reaction vessel) is not particularly limited. That is, the order of introduction may be arbitrary. Therefore, the reaction solvent may be added to the reaction system in advance, and the nitrobenzene compound, the alkali metal dithionite and, if necessary, the alkali metal carbonate may be introduced into the reaction system at the same time. Alternatively, the alkali metal dithionite which is diluted with the reaction solvent as necessary may be dispersed by stirring, and then the nitrobenzene compound dissolved in the reaction solvent as necessary may be introduced into the reaction system. In addition, the two may be introduced into the reaction system in the opposite manner. In this case, the alkali metal carbonate to be used as needed may be present together with the nitrobenzene compound, may be present together with the alkali metal dithionite, or may be introduced into the reaction system separately from these. In addition, the reaction solvent may contain water and/or an aprotic polar solvent.
When the N-protected nitrobenzene compound is used, it is preferably introduced into the reaction system in the following manner. Specifically, it is preferable that the alkali metal dithionite is dispersed (dissolved) in a reaction solvent containing an aprotic polar solvent by stirring in the reaction system, and then the N-protected nitrobenzene compound dissolved in the reaction solvent containing an aprotic polar solvent is introduced (added) into the reaction system. In this case, it is preferable that the reaction solvent in which the N-protected nitrobenzene compound is dissolved contains water.
(reaction temperature)
The reaction temperature may be appropriately determined depending on the solvent used. Specifically, the reflux temperature of the reaction solvent is preferably 0 ℃ or higher and is preferably not higher than: a state containing the above nitrobenzene compound, an alkali metal salt of dithionous acid and, if necessary, an alkali metal carbonate. More specifically, it is preferably 20 ℃ to 150 ℃, more preferably 50 ℃ to 120 ℃, and particularly preferably 60 ℃ to 100 ℃. When the reaction is carried out at such a temperature, an aminobenzene compound having a higher purity can be obtained.
(other conditions)
In the present invention, the following conditions are preferably employed as other reaction conditions. The reaction time may be appropriately determined depending on the consumption amount of the nitrobenzene compound, the amount of the aminonitrobenzene compound produced, the scale of the reaction, and the like, and may be usually 30 minutes to 10 hours.
In the present invention, the reaction atmosphere is not particularly limited, and may be any atmosphere under an air atmosphere, an inert gas atmosphere, or a hydrogen atmosphere. Among them, in consideration of handling properties, the atmosphere is preferably an air atmosphere.
The reaction system may be any one of atmospheric pressure, pressurized pressure and reduced pressure. Among them, it is preferably carried out under atmospheric pressure.
(method of purifying and removing aminobenzene Compound)
By carrying out the reaction under the above conditions, the nitrobenzene compound can be changed to an aminobenzene compound (diaminobenzene compound or N-protected aminobenzene compound) represented by the following formula (2).
(wherein n is an integer of 1 to 4, preferably 1,
R1and RAThe same as defined in said formula (1). )
In the formula (2), R1And RAThe same as defined in said formula (1). Of course, R1The preferable position and substituent of (2) are also the same as those of the nitrobenzene compound. Therefore, R is preferred1Bonding with the 1 st carbon atom to obtain 2, 3-diaminobenzene compound or 2-N-protected amino-3-aminobenzene compound. RAIn the case of a hydrogen atom, the number of steps can be reduced because the diaminobenzene compound represented by the following formula (2 ") can be obtained directly.
For the aminobenzene compound obtained from the reaction conditions, it is preferable to take out from the reaction system in the following manner. Specifically, it is preferable to contact the obtained reaction solution with a sparingly water-soluble organic solvent such as ethyl acetate or methylene chloride, and extract the aminobenzene compound with the sparingly water-soluble organic solvent. Then, it is preferable to wash the organic solvent which is hardly soluble in water and contains the above-mentioned aminobenzene compound with water to remove the alkali metal salt of dithionous acid and the carbonate used as needed.
In the washing and extraction operation, the N-protected diaminobenzene compound represented by the following formula (2') is advantageous.
(wherein n is an integer of 1 to 4, preferably 1,
R1as defined in said formula (1),
RA1as the protecting group, specifically preferred is a tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylmethoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, formyl group, acetyl group, tosyl group or nitrobenzenesulfonyl group. )
That is, a diaminobenzene compound represented by the following formula (2') (R in the formula (2))AA hydrogen atom-containing compound), the N-protected diaminobenzene compound is more soluble in the water-insoluble organic solvent, and the purity can be easily improved by washing with water.
(wherein n is an integer of 1 to 4, preferably 1,
R1the same as defined in said formula (1). )
In the present invention, the alkali metal salt of dithionous acid and the alkali metal carbonate used as necessary are inorganic salts and can be easily removed by washing with water. The aminobenzene compound can be obtained in high purity by washing with water.
The obtained aminobenzene compound can be further purified by a known method such as recrystallization and column separation.
(method for obtaining a diaminobenzene compound from an N-protected aminobenzene compound)
In the present invention, when the above-mentioned N-protected nitrobenzene compound is used, an N-protected diaminobenzene compound represented by the following formula (2') can be obtained.
(wherein n is an integer of 1 to 4, preferably 1,
R1as defined in said formula (1),
RA1is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, formyl, acetyl, tosyl or nitrobenzenesulfonyl. )
From the N-protected diaminobenzene compound, a diaminobenzene compound represented by the following formula (2') can be easily obtained.
(wherein n is an integer of 1 to 4, preferably 1,
R1the same as defined in said formula (1). )
In particular, the method of manufacturing a semiconductor device,the deprotection reaction can be carried out by contacting the N-protected aminobenzene compound with an acid, a base or hydrogen. And a diaminobenzene compound represented by the formula (2') is obtained. As preferred compounds, R is preferred1Bonding with the 1 st carbon atom to obtain the 2, 3-diaminobenzene compound.
In the present invention, as the acid used for removing the protecting group, a known acid can be used. Specific examples thereof include hydrochloric acid, sulfuric acid, hydrobromic acid, and methanesulfonic acid. Among them, hydrochloric acid is preferably used from the viewpoint of workability.
In the present invention, the amount of the acid used is not particularly limited, but is preferably 0.1 to 100 moles, and more preferably 1 to 10 moles, based on 1 mole of the N-protected aminobenzene compound.
As the base used for removing the protecting group, a known base can be used. Specific examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide and barium hydroxide, organic bases such as piperidine and morpholine, and salts such as potassium thiophenol salts. Among them, from the viewpoint of workability, inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as piperidine are preferably used.
In the present invention, the amount of the base used is not particularly limited, and is preferably 0.1 to 100 moles, and more preferably 1 to 10 moles, based on 1 mole of the N-protected aminobenzene compound.
Examples of hydrogen used for the purpose of removing the protecting group include hydrogen gas and compounds generating hydrogen gas. When hydrogen is used, a palladium catalyst is preferably used. Specifically, it is preferable to remove the protecting group by hydrogen reduction in the presence of hydrogen, formic acid, formate salt or the like in the presence of a palladium catalyst. Among them, palladium on carbon and hydrogen are preferably used from the viewpoint of operability.
In the present invention, when a palladium catalyst is used, the amount thereof is not particularly limited, and is preferably 0.001 to 0.5 mol, and more preferably 0.01 to 0.1 mol, based on 1 mol of the N-protected aminobenzene compound. The hydrogen is not particularly limited as long as it is in an amount sufficient for reduction. For example, when formic acid is used, it is preferable to use 1.0 to 10 moles of formic acid per 1 mole of the N-protected aminobenzene compound.
In the present invention, in order to carry out the deprotection reaction, it is preferable to mix the N-protected aminobenzene compound and an acid, a base or hydrogen by stirring in order to bring them into contact with each other. The mixing with stirring is preferably carried out in a solvent. The solvent used is not particularly limited as long as it does not affect the N-protected aminobenzene compound and the acid or the base. Specific examples thereof include water, methanol, ethanol, toluene, THF (tetrahydrofuran), dioxane, and the like.
When the N-protected aminobenzene compound and the acid or the base are stirred and mixed in the reaction system, the order of introducing the both into the system is not particularly limited. The N-protected aminobenzene compound diluted with a solvent as necessary may be introduced into the reaction system together with an acid or a base, or one of the N-protected aminobenzene compound diluted with a solvent as necessary may be introduced into the reaction system first, and the other one diluted with a solvent as necessary may be added to the reaction system. Among them, in order to more smoothly perform the deprotection reaction, it is preferable that the N-protected aminobenzene compound diluted with a solvent as necessary is introduced into the reaction system, and then an acid or a base diluted with a solvent as necessary is added to the system.
The temperature for the deprotection reaction is not particularly limited, but is preferably 0 to 200 ℃ and more preferably 5 to 120 ℃. The reaction time is not particularly limited, and may be appropriately determined depending on the amount of the diaminobenzene compound produced. The atmosphere is also not particularly limited, and may be either an air atmosphere or an inert gas atmosphere. Among them, in consideration of handling properties, the atmosphere is preferably an air atmosphere.
The reaction system may be any one of atmospheric pressure, pressurized pressure and reduced pressure. Among them, it is preferably carried out under atmospheric pressure.
In the present invention, the deprotection reaction is preferably carried out under the conditions as described above. After the deprotection reaction is completed, an acid, an alkali, or the like may be removed by washing with water or the like. The diaminobenzene compound thus obtained can be further purified by a known method such as recrystallization and column separation.
Next, a method for producing a benzimidazole derivative by reacting the obtained diaminobenzene compound with an orthoester derivative in the presence of an acid will be described. The reaction of the diaminobenzene compound with the orthoester derivative is known per se, and the method described in patent document 1 and the like can be used.
(ortho ester derivative)
By using R of said formula (1)AAn aminonitrobenzene compound being a hydrogen atom to give R of said formula (2)AA diaminobenzene compound which is a hydrogen atom. Further, as described above, by carrying out a deprotection reaction, a diaminobenzene compound represented by the formula (2 ") is obtained. Needless to say, R in the above formula (2)AThe diaminobenzene compound which is a hydrogen atom is the same compound as the diaminobenzene compound represented by the formula (2 ").
In the present invention, the orthoester derivative reacted with the diaminobenzene compound is represented by the following formula (3).
In the formula, R2Is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. R2When the alkoxy group is a compound having four alkoxy groups. Wherein, in order to use the obtained benzimidazole derivative as an intermediate of candesartan cilexetil, R2Ethoxy is preferred.
R3The alkyl groups are C1-C6 alkyl groups, which may be the same or different.
Commercially available products can be used as the orthoester derivative.
In the reaction of the diaminobenzene compound and the orthoester derivative, the amount of the orthoester derivative used is not particularly limited, but is preferably 0.5 to 10 moles, and more preferably 0.95 to 2 moles, based on 1 mole of the diaminobenzene compound.
(acid)
The reaction of the diaminobenzene compound with the ortho ester derivative is carried out in the presence of an acid, which is not particularly limited, and inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid can be used, and among them, organic acids such as acetic acid are preferably used from the viewpoint of ease of handling. In this case, the acid used may be used as a reaction solvent.
The amount of the acid to be used is not particularly limited, and may be added in excess when the acid is used as a reaction solvent. However, considering post-treatment after the reaction, etc., the amount of the acid used is preferably 0.5 to 10mL, more preferably 0.5 to 5mL, based on 1g of the diaminobenzene compound. When an organic solvent is used as the reaction solvent, the amount is preferably 0.1 to 10 moles, more preferably 0.5 to 3 moles, based on 1 mole of the diaminobenzene compound, in consideration of the reaction progressivity, post-treatment, and the like.
(production conditions of benzimidazole derivative)
In the present invention, the diaminobenzene compound and the orthoester derivative may be brought into sufficient contact with each other in an atmosphere in which an acid is present.
When an organic solvent is used as the reaction solvent, there is no particular limitation as long as the diaminobenzene compound, the acid, and the orthoester derivative are not adversely affected. However, in order to increase the reaction temperature, shorten the reaction time, and facilitate the post-treatment, the solvent is preferably ethyl acetate, toluene, Tetrahydrofuran (THF), or the like, and particularly preferably toluene.
The reaction of the diaminobenzene compound with the orthoester derivative is: condensation reaction of the amino group and the alkoxy group occurs, followed by cyclization reaction, to obtain the benzimidazole derivative represented by the following formula (4).
(wherein n is an integer of 1 to 4, preferably 1,
R1as defined in said formula (1),
R2the same as defined in said formula (3). )
R1The preferable position and substituent of (2) are also the same as those of the nitrobenzene compound.
In the present reaction, the reaction temperature may be appropriately determined according to the reaction conditions set, and is preferably 0 to 150 ℃, more preferably 10 to 100 ℃, and particularly preferably 10 to 50 ℃. When the amount of the impurity is within the above range, the amount of the impurity generated as a by-product in the reaction can be reduced. In addition, the reaction time is preferably 0.5 to 5 hours. The atmosphere is not particularly limited, and may be an air atmosphere. The reaction may be carried out under any of reduced pressure, increased pressure and atmospheric pressure.
The obtained benzimidazole derivative may be removed from the reaction system by a known method. The benzimidazole derivative can be purified by a known method.
The obtained benzimidazole derivative is suitable for use as an intermediate (raw material) of a sartan prodrug such as candesartan cilexetil.
Examples
The present invention will be described in detail below with reference to examples, but these are merely specific examples, and the present invention is not limited thereto.
The purity evaluation in the examples was performed by using the following method of High Performance Liquid Chromatography (HPLC).
< measurement conditions of HPLC >
The device comprises the following steps: high Performance Liquid Chromatography (HPLC)
Model: 2695-2489-2998 (produced by Waters corporation)
A detector: ultraviolet absorption spectrometer (measuring wavelength: 210nm)
Column: kromasil C18, inner diameter 4.6mm, length 15cm (particle size 5 μm)
(manufactured by Akzo Nobel Co., Ltd.)
Column temperature: constant at 30 ℃
Sample temperature: constant at 25 deg.C
Mobile phase A: acetonitrile
Mobile phase B: 15mM potassium dihydrogen phosphate in water (pH 2.5 adjusted with phosphoric acid)
Liquid supply of mobile phase: concentration gradient control was performed by changing the mixing ratio of the mobile phase A, B as shown in table 1 below.
Flow rate: 1.0 mL/min
Measuring time: 40 minutes
TABLE 1
| Time after injection (minutes) | Mobile phase A (vol%) | Mobile phase B (vol%) |
| 0～30 | 60→40 | 40→60 |
| 30～90 | 40 | 60 |
Under the above conditions, a peak was confirmed at about 11.4 minutes for methyl 2-amino-3-nitrobenzoate (the 2-amino-3-nitrobenzene compound), about 2.6 minutes for methyl 2, 3-diaminobenzoate (the 2, 3-diaminobenzene compound), about 19.1 minutes for methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (the N-protected nitrobenzene compound), and about 4.0 minutes for methyl 2-ethoxy-1H-benzimidazole-7-carboxylate (the benzimidazole derivative).
In the following examples, the purity of each of the 2-amino-3-nitrobenzene compound, the N-protected nitrobenzene compound, the 2, 3-diaminobenzene compound, and the benzimidazole derivative is: the ratio of the peak area value of each compound to the sum of the area values of all peaks (excluding the solvent-derived peak) measured under the above conditions.
Example 1 (example of producing diaminobenzene Compound Using aminonitrobenzene Compound)
The reaction of the following formula was carried out.
In a mixed solvent (reaction solvent) of Dimethylformamide (DMF) (4ml), water (0.367ml, 20.4mmol) and toluene (3ml), methyl 2-amino-3-nitrobenzoate (1.0g, 5.1 mmol; 2-amino-3-nitrobenzene compound), sodium dithionite (purity 80 mass%) (3.33g, 15.3mmol ((number of moles of sodium dithionite calculated from purity); manufactured by Wako pure chemical industries, Ltd., alkali metal salt of dithionous acid), potassium carbonate (1.4g, 10.2 mmol; alkali metal carbonate) were mixed with stirring at a reaction temperature of 100 ℃ for 4 hours (reaction time).
Water (14mL) was added to the obtained reaction solution, and then the mixture of the obtained reaction solution and water was extracted with ethyl acetate (5 mL). Extraction based on this ethyl acetate (5ml) was repeated 5 times. The ethyl acetate solution (total 25ml) was washed with water and concentrated under reduced pressure to give the desired product methyl 2, 3-diaminobenzoate (0.72g, 2, 3-diaminobenzene compound; yield by mass: 85%, conversion of aminonitrobenzene compound by High Performance Liquid Chromatography (HPLC) 100%). The purity of methyl 2, 3-diaminobenzoate confirmed by HPLC was 94.0%, and the purity of polar impurities (presumably, a compound having a sulfo group at the 5-position (methyl 2, 3-diamino-5-sulfobenzoate)) was 2.2%. The analytical values of methyl 2, 3-diaminobenzoate are as follows.
IR(KBr)1693cm-1。
1H-NMR(CDCl3)δ7.30-7.80(m，1H)，6.40-7.10(m.2H)，1.45(brs，2H)，3.85(s，3H)，3.40(brs，2H)。
Example 2 (example of producing diaminobenzene Compound Using aminonitrobenzene Compound)
The same operation as in example 1 was carried out except that sodium dithionite (purity 80 mass%) was used (2.22g, 10.2mmol ((number of moles of sodium dithionite calculated from purity); and alkali metal salt of dithionite manufactured by Wako pure chemical industries, Ltd.) in example 1 and the reaction time was 5 hours, the conversion was 10%, and no polar impurities were observed.
Example 3 (example of producing diaminobenzene Compound Using aminonitrobenzene Compound)
The same operation as in example 1 was carried out, except that the reaction solvent used in example 1 was a mixed solvent of DMF (7ml) and water (0.099ml, 5.1 mmol). The yield of methyl 2, 3-diaminobenzoate was 94%. The conversion was 100%. In addition, the purity of methyl 2, 3-diaminobenzoate confirmed by HPLC was 95.4%, and the polar impurity was 2.5%. The analysis result of the obtained methyl 2, 3-diaminobenzoate was the same as in example 1.
Example 4 (example of producing diaminobenzene Compound Using aminonitrobenzene Compound)
The same operation as in example 1 was carried out except for using 7ml of DMF as a reaction solvent in example 1. The yield of methyl 2, 3-diaminobenzoate was 94%. The conversion was 100%. In addition, the purity of methyl 2, 3-diaminobenzoate confirmed by HPLC was 97.5%, and no polar impurities were confirmed.
Example 5 (example of production of diaminobenzene Compound Using aminonitrobenzene Compound)
Relative to example 1, except that 15 normal ammonia (2.55ml, NH) was used338.3mmol) was carried out in the same manner as in example 1 except that potassium carbonate and the reaction solvent were replaced. The conversion was 21.5%. In addition, no polar impurities were observed.
Example 6 (example of production of diaminobenzene Compound Using N-protected Nitrobenzene Compound; reduction reaction and deprotection reaction)
The reaction of the following formula was carried out. The reduction and deprotection reactions are shown together.
(reduction reaction)
A solution of sodium dithionite (purity 80 mass%) (12.5g, 57.5mmol) in DMF (25mL) was stirred at 100 ℃ for 30 minutes. To the solution was added dropwise a solution containing methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (5g, 16.9mmol, N-protected nitrobenzene compound), DMF (15mL) and water (1.4mL, 77.8mmol) over 1 hour. After reacting (stirring and mixing) at 100 ℃ for 2 hours, toluene (30m) and water (1000ml) were added to the reaction solution. After a 24 mass% aqueous solution of sodium hydroxide was added to the mixture to adjust the pH to 8.20, the product was extracted with ethyl acetate (30 ml). The extraction was performed 4 times in total. Thereafter, the ethyl acetate solutions used in the extraction were combined and washed 3 times with water (80 ml). The ethyl acetate solution after washing was confirmed by High Performance Liquid Chromatography (HPLC), and as a result, the conversion was 100%. Further, the purity of methyl 2-t-butoxycarbonyl-2, 3-diaminobenzoate (N-protected aminobenzene compound) was 97.9%. No polar impurities were identified.
(deprotection reaction)
Methanol (50ml) and concentrated hydrochloric acid (5.1g, 51mmol) were added to a solution of methyl 2-t-butoxycarbonyl-2, 3-diaminobenzoate in ethyl acetate, and the mixture was stirred at 50 ℃ for 8 hours. Thereafter, the reaction solution was diluted with water (200ml), and a 24 mass% aqueous sodium hydroxide solution was added to adjust the pH to 8.8. The mixture at pH8.8 was subjected to liquid separation, and the aqueous layer was extracted 4 times with ethyl acetate (30 mL). The original organic layer separated from the mixture at pH8.8 was combined with the extract (ethyl acetate) and washed 4 times with water (80 mL). The obtained organic layer was concentrated under reduced pressure to obtain methyl 2, 3-diaminobenzoate (2.4g, 2, 3-diaminobenzene compound, yield by mass: 85.7%).
Example 7 reaction of diaminobenzene Compound with ortho ester derivative
The reaction of the following formula was carried out.
Methyl 2, 3-diaminobenzoate (0.70g, 4.21 mmol; 2, 3-diaminobenzene compound) obtained in example 4 was dissolved in toluene (1mL), tetraethoxymethane (0.81g, 4.21 mmol; orthoester derivative; acetic acid (0.25g, 4.21 mmol; acid) was added in this order at normal temperature, and then the mixture was reacted at 100 ℃ for 2 hours. Water (5mL) was added to the reaction mixture, and the mixture was crystallized and filtered to give methyl 2-ethoxy-1H-benzimidazole-7-carboxylate (742mg, yield: 80%). The purity of 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester confirmed by HPLC was 96.7%.
Example 8 (example of production of benzimidazole derivative Using N-protected Nitrobenzene Compound)
(reduction reaction; Synthesis of N-protected aminobenzene Compound)
Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (20g, 67.50mmol, N-protected nitrobenzene compound) was weighed into a 500mL four-necked flask equipped with a two-bladed stirring paddle having a diameter of 7.5cm, DMF (60mL), sodium dithionite (purity 80 mass%) (27.7g, 135.01mmol), and water (4.9mL, 270.01mmol) were added, and the reaction was continued for 6 hours under stirring at 60 ℃. Toluene (200mL) was added to the reacted solution to extract the solution, and then the organic layer was washed 2 times with 1N NaOH (200 mL). The organic layer was washed 1 more time with water (200 mL). The washed toluene solution was confirmed by High Performance Liquid Chromatography (HPLC), and the conversion of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (N-protected nitrobenzene compound) was 100%. Further, the purity of methyl 2-tert-butoxycarbonyl-2, 3-diaminobenzoate was 98.0%. No polar impurities were identified.
(deprotection reaction; Synthesis of diaminobenzene Compound)
Concentrated hydrochloric acid (15g, 150mmol) was added to a toluene solution containing methyl 2-t-butoxycarbonyl-2, 3-diaminobenzoate, and the mixture was reacted at 50 ℃ for 3 hours. Thereafter, a 1-normal aqueous solution of sodium hydroxide (150mL) was added to adjust the pH to about 9. The mixture was subjected to liquid separation, and the obtained organic layer was washed with water (100mL) 2 times. The obtained organic layer was concentrated under reduced pressure to obtain methyl 2, 3-diaminobenzoate (9.9g, 2, 3-diaminobenzene compound, yield by mass: 88.3%) as a residue.
(condensation, cyclization reaction; Synthesis of benzimidazole derivative)
To the methyl 2, 3-diaminobenzoate residue (9.9g) were added acetic acid (40mL) and tetraethoxymethane (12.98g, 67.50 mmol; orthoester derivative) and reacted at 20 ℃ for 3 hours. After the reaction solution was cooled, 14% aqueous ammonia (120mL) was added to crystallize 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester by neutralization. The resulting slurry was filtered under reduced pressure, and the precipitated crystals were separated and recovered, followed by drying under reduced pressure at 40 ℃ to give methyl 2-ethoxy-1H-benzimidazole-7-carboxylate (11.3g, yield: 86%). The purity of methyl 2-ethoxy-1H-benzimidazole-7-carboxylate was confirmed by HPLC to be 99.6%.
Claims (8)
1. A process for producing a diaminobenzene compound or an N-protected aminobenzene compound represented by the following formula (2) by bringing an aminonitrobenzene compound or an N-protected nitrobenzene compound represented by the following formula (1) into contact with an alkali metal salt of dithionous acid,
in the formula (1), n is an integer of 1 to 4,
R1is alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, acyloxy group having 2 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, nitro group or halogen atom, when n is not less than 2, a plurality of R are1Optionally the same or different from each other,
RAis a hydrogen atom or a protecting group;
in the formula (2), R1、RAAnd n is as defined in said formula (1).
2. The method according to claim 1, characterized in that the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the formula (1) is contacted with the alkali metal salt of dithionous acid in a reaction solvent containing an aprotic polar solvent.
3. The method according to claim 2, wherein the reaction solvent contains water in an amount of 1 to 3 moles based on 1 mole of the alkali metal salt of dithionous acid.
4. The method according to any one of claims 1 to 3, wherein the aminonitrobenzene compound or the N-protected nitrobenzene compound represented by the formula (1) is contacted with the alkali metal salt of dithionous acid in the presence of an alkali metal carbonate.
5. The method according to any one of claims 1 to 4, wherein the alkali metal dithionite is used in an amount of 1 to 5 moles based on 1 mole of the aminonitrobenzene compound or N-protected nitrobenzene compound represented by formula (1).
6. The method according to any one of claims 1 to 5, wherein in the formulae (1) and (2),
RAthe protecting group of (A) is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, formyl, acetyl, tosyl or nitrobenzenesulfonyl.
7. A process for producing a diaminobenzene compound represented by the following formula (2 ') which comprises producing an N-protected aminobenzene compound represented by the following formula (2') by the process according to claim 6, and then bringing the obtained N-protected aminobenzene compound into contact with an acid, a base or hydrogen,
in the formula (2'), R1And n is as defined in said formula (1),
RA1is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, formyl, acetyl, tosylA radical or a nitrobenzenesulfonyl radical,
n is an integer of 1 to 4;
in the formula (2'), R1And n is as defined in said formula (1).
8. A process for producing a benzimidazole derivative represented by the following formula (4), which comprises producing a diaminobenzene compound represented by the formula (2) or (2 ") by the process according to any one of claims 1 to 5 and 7, and then reacting the diaminobenzene compound thus obtained with an orthoester derivative represented by the following formula (3) in the presence of an acid,
in the formula (3), R2An alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms,
R3is alkyl with 1-6 carbon atoms, and is optionally the same or different;
in the formula (4), R1And n is as defined in said formula (1),
R2the same as defined in said formula (3).
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015134A1 (en) * | 2004-07-28 | 2006-02-09 | Dr. Reddy's Laboratories Ltd. | Process for preparing candesartan cilexetil |
| CN101595110A (en) * | 2006-11-16 | 2009-12-02 | 法马科皮亚有限公司 | Be used for immunosuppressant 7-substituted purin derivatives |
| WO2011112731A2 (en) * | 2010-03-10 | 2011-09-15 | Kalypsys, Inc. | Heterocyclic inhibitors of histamine receptors for the treatment of disease |
| US20120225900A1 (en) * | 2009-11-10 | 2012-09-06 | Pfizer Inc. | N2-pyrazolospiroketone acetyl-coa carboxylase inhibitors |
| US20130274243A1 (en) * | 2012-02-03 | 2013-10-17 | Pfizer Limited | Chemical Compounds |
| CN103539659A (en) * | 2013-10-23 | 2014-01-29 | 东南大学 | 2,4-dibenzyloxybenzoic acid derivative and preparation method and application thereof |
| CN103724276A (en) * | 2013-12-13 | 2014-04-16 | 成都丽璟科技有限公司 | Novel method for preparing benzimidazole compounds from nitroaniline |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2010358561B2 (en) | 2010-08-04 | 2016-06-02 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| KR20170001962A (en) | 2014-05-15 | 2017-01-06 | 제이 파마 가부시끼가이샤 | An anticancer agent composition |
-
2018
- 2018-05-15 WO PCT/JP2018/018703 patent/WO2018212162A1/en active Application Filing
- 2018-05-15 CN CN201880031471.5A patent/CN110621652A/en not_active Withdrawn
- 2018-05-15 JP JP2019518793A patent/JPWO2018212162A1/en not_active Ceased
- 2018-05-15 KR KR1020197032872A patent/KR20200009001A/en unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015134A1 (en) * | 2004-07-28 | 2006-02-09 | Dr. Reddy's Laboratories Ltd. | Process for preparing candesartan cilexetil |
| CN101595110A (en) * | 2006-11-16 | 2009-12-02 | 法马科皮亚有限公司 | Be used for immunosuppressant 7-substituted purin derivatives |
| US20120225900A1 (en) * | 2009-11-10 | 2012-09-06 | Pfizer Inc. | N2-pyrazolospiroketone acetyl-coa carboxylase inhibitors |
| WO2011112731A2 (en) * | 2010-03-10 | 2011-09-15 | Kalypsys, Inc. | Heterocyclic inhibitors of histamine receptors for the treatment of disease |
| US20130274243A1 (en) * | 2012-02-03 | 2013-10-17 | Pfizer Limited | Chemical Compounds |
| CN103539659A (en) * | 2013-10-23 | 2014-01-29 | 东南大学 | 2,4-dibenzyloxybenzoic acid derivative and preparation method and application thereof |
| CN103724276A (en) * | 2013-12-13 | 2014-04-16 | 成都丽璟科技有限公司 | Novel method for preparing benzimidazole compounds from nitroaniline |
Non-Patent Citations (4)
| Title |
|---|
| M. JONATHAN FRAY等: "Structure-Activity Relationships of 1,4-Dihydro-(1H,4H)-quinoxaline- 2,3-diones as N-Methyl-D-aspartate (Glycine Site) Receptor Antagonists. 1. Heterocyclic Substitude 5-Alkyl Derivatives", 《J. MED. CHEM.》 * |
| MASAHIRO FUKUZUMI等: "Synthesis of ortho-Phenylenebis(guanidine) Derivatives with Potential Chirality", 《HELVETICA CHIMICA ACTA》 * |
| N. I. AVDYUNINA等: "evelopment of synthesis technology for the selective anxiolytic drug afobazole", 《PHARMACEUTICAL CHEMISTRY JOURNAL》 * |
| 高勇等: "3,4-二氨基苯乙酸的合成", 《化学试剂》 * |
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Application publication date: 20191227 |