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WO2017209035A1 - Procédé de production d'un dérivé de biphényle benzimidazole - Google Patents

Procédé de production d'un dérivé de biphényle benzimidazole Download PDF

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Publication number
WO2017209035A1
WO2017209035A1 PCT/JP2017/019877 JP2017019877W WO2017209035A1 WO 2017209035 A1 WO2017209035 A1 WO 2017209035A1 JP 2017019877 W JP2017019877 W JP 2017019877W WO 2017209035 A1 WO2017209035 A1 WO 2017209035A1
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Prior art keywords
group
represented
formula
derivative
reaction
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English (en)
Japanese (ja)
Inventor
雅彦 関
史哲 岩崎
山本　博将
森　博志
健次 田中
吉貴 清家
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Tokuyama Corp
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Tokuyama Corp
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Priority to CN201780033164.6A priority Critical patent/CN109195952A/zh
Priority to KR1020187032831A priority patent/KR20190015225A/ko
Priority to JP2018520889A priority patent/JP6938001B2/ja
Publication of WO2017209035A1 publication Critical patent/WO2017209035A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel method for producing biphenylbenzimidazole derivatives useful as pharmaceutical intermediates.
  • R, R ′, R ′′, and z differ depending on the corresponding drug substance.
  • R is a tetrazol-5-yl group
  • R ′ is an ethoxy group
  • R ′′ is a 7- (cilexetyloxycarbonyl) group
  • the drug substance is candesartan cilexetil. is there.
  • R is a 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group
  • R ′ is an ethoxy group
  • R ′′ is a carboxyl group
  • the drug substance is azilsartan.
  • R is a 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group
  • R ′ is an ethoxy group
  • R ′′ is a medoxomiloxycarbonyl group.
  • the drug substance is azilsartan medoxomil.
  • candesartan cilexetil is produced by a method represented by the following reaction formula (see Patent Document 1, etc.).
  • the process for producing the intermediate is also important. That is, since the drug substance finally obtained is obtained through many steps, the yield and purity of each intermediate greatly affect the quality of the drug substance or the manufacturing cost. For this reason, various investigations have been made on the method for producing the intermediate.
  • Patent Document 1 Many production methods are known for the cyanobiphenylbenzimidazole derivative represented by the above formula (see, for example, Non-Patent Document 1). Specifically, Patent Document 2 and Non-Patent Document 1 describe processes for carrying out reactions of nitration, Curtius rearrangement, cyanobiphenylation, reduction, and cyclization from o-phthalic acid. . In this method, each reaction is performed on the compound obtained in the previous step, and there are problems such as a decrease in total yield and an increase in cost due to an increase in the basic unit of expensive reagents. Therefore, it has been desired to develop an inexpensive manufacturing method that reduces the number of continuous steps.
  • Patent Documents 3 and 4 include a method for producing the cyanobiphenylbenzimidazole derivative by reacting the benzimidazole derivative and the cyanobiphenyl bromide in the presence of a base in methanol or ethanol. It is shown.
  • Patent Document 1 a method of reacting a compound in which a cyano group is replaced with a tetrazolyl group protected with a triphenyl group in the biphenyl compound and the benzimidazole derivative. 5, see Non-Patent Document 1). Specifically, a method is described in which this reaction is carried out in dimethylformamide in the presence of a base.
  • a compound in which a cyano group is replaced with a tetrazolyl group protected with a benzyl group and the benzimidazole derivative are mixed with an alcohol (for example, methanol or isopropyl alcohol), dimethylformamide, dimethyl in the presence of a base.
  • an alcohol for example, methanol or isopropyl alcohol
  • dimethylformamide dimethyl in the presence of a base.
  • a method of reacting in a solvent such as acetamide is also known (see Non-Patent Document 2, Patent Documents 6 and 7).
  • Patent Document 6 a trityl group is also mentioned as a protective group.
  • Patent No. 2514282 International Publication No. 2013/114305 Chinese Patent Application No. 1027616638 International Publication No. 2006/015134 Chinese Patent Application No. 1013223610 International Publication No. 2014/034868 International Publication No. 2014/051008
  • the biphenylbenzimidazole derivative can be produced with fewer steps.
  • the conventional method has a problem that the yield of the biphenylbenzimidazole derivative is low.
  • a cyanobiphenyl compound is bonded to a nitrogen atom which is not a nitrogen atom to be reacted with a cyanobiphenyl compound among the two nitrogen atoms of the benzimidazole derivative.
  • the production rate of the isomer represented by may increase. Since this isomer is a compound similar to the target product, when the next reaction is carried out with the isomer included, impurities different from the target product are further generated as a by-product. Therefore, it is desired that such an isomer has a small amount of by-product even if it is an intermediate.
  • Patent Documents 3 and 4 do not describe that the obtained cyanobiphenylbenzimidazole derivative contains the ether by-product. Patent Document 3 also does not describe that the obtained cyanobiphenylbenzimidazole derivative contains the isomer.
  • the ether by-product is often present in the reaction solution before taking out the cyanobiphenylbenzimidazole derivative from the reaction system, that is, after completion of the reaction. It was confirmed that the isomer was also contained. In the above method and the like, it is considered that a crystallization method in which the loss of the cyanobiphenylbenzimidazole derivative is increased in order to remove this ether by-product and isomers.
  • Patent Documents 6 and 7 the above-mentioned problem of ether by-products and the problem of isomers may occur.
  • a hydrogen source such as hydrogen gas or formic acid is used in the deprotection reaction performed in the final step of the drug substance production. It was necessary to use ammonium / palladium metal or the like. For this reason, when industrial production of candesartan cilexetil is carried out, it is possible to prevent the explosion of hydrogen gas and enhance safety, or to prevent the introduction of harmful metals into the final product (the drug substance). Therefore, there is room for improvement in that strict control is required.
  • an object of the present invention is to provide a production method capable of suppressing the production of the ether by-product and improving the yield of the target biphenylbenzimidazole derivative.
  • the inventors of the present invention made extensive studies to solve the above problems.
  • a deprotection reaction or reaction in a post-process ie, a process after manufacturing the biphenylbenzimidazole in the manufacture of the drug substance
  • the biphenyl compound is converted to a cyano group or 1-trityl-
  • Various studies were conducted focusing on compounds having a 1H-tetrazol-5-yl group.
  • Various studies were conducted to suppress the production of the ether by-product and isomer.
  • a reaction solvent that hardly reacts with the biphenyl bromide (halide) and that can increase the yield of the biphenylbenzimidazole derivative was examined.
  • the first aspect of the present invention is (1) in the presence of a base, Following formula (1)
  • R 1 is an alkyl group having 1 to 6 carbon atoms
  • R 2 is an alkyl group having 1 to 6 carbon atoms, a cilexetil group, or a medoxomil group.
  • R 3 , R 4 , and R 5 are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an alkyloxyalkyl group having 2 to 12 carbon atoms
  • R 3 , R 4 , and R 5 are not hydrogen atoms at the same time.
  • the first aspect of the present invention can take the following aspects.
  • the branched alcohol is at least one selected from the group consisting of isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, and 3-pentanol.
  • the branched alcohol is a secondary alcohol.
  • the reaction solvent further contains a polar solvent (excluding the branched alcohol represented by the formula (4)).
  • R 6 is an alkyl group having 1 to 12 carbon atoms, and the plurality of R 6 may be the same group or different groups.
  • the second aspect of the present invention is (6) A step of producing the biphenylbenzimidazole derivative by the production method of any one of (1) to (5),
  • the benzimidazole derivative is represented by the following formula (1 ′)
  • a benzimidazole derivative represented by The biphenyl compound is represented by the following formula (2 ′)
  • Tr is a triphenylmethyl group (also referred to as “trityl group”), and X has the same meaning as in formula (2).
  • a biphenyl compound represented by The biphenylbenzimidazole derivative is represented by the following formula (3 ′)
  • trityl candesartan represented by the formula (hereinafter sometimes simply referred to as “trityl candesartan”), and by introducing a cilexetil group into the trityl candesartan, the following formula (7):
  • Et is an ethyl group
  • Tr is a triphenylmethyl group.
  • the third aspect of the present invention is (7)
  • the fourth aspect of the present invention is (8) A step of producing the biphenylbenzimidazole derivative by the production method of any one of (1) to (5),
  • the benzimidazole derivative is represented by the following formula (1 ′)
  • a benzimidazole derivative represented by The biphenyl compound is represented by the following formula (2 ′)
  • Tr is a triphenylmethyl group, and X has the same meaning as in formula (2).
  • a biphenyl compound represented by The biphenylbenzimidazole derivative is represented by the following formula (7)
  • a biphenylbenzimidazole derivative which is an intermediate of a sultan based drug substance such as candesartan or azilsartan, can be obtained in a state where the conversion rate of the benzimidazole derivative is high and the ether by-product is small. Can do. That is, a biphenylbenzimidazole derivative can be obtained with a high yield.
  • a biphenylbenzimidazole derivative can be obtained with a high yield.
  • candesartan cilexetil can be produced in a shorter process.
  • candesartan cilexetil can be produced in a particularly short process.
  • benzimidazole derivative represented by the above formula (1) (hereinafter sometimes simply referred to as “benzimidazole derivative”) and a biphenyl compound represented by the above formula (2) (hereinafter, it may be simply referred to as “biphenyl compound”) and may be described as a biphenylbenzimidazole derivative represented by the above formula (3) (hereinafter simply referred to as “biphenylbenzimidazole derivative”).
  • the reaction solvent containing a branched alcohol having a specific structure hereinafter, this reaction is also referred to as “the reaction of the present invention”). It is characterized by doing.
  • the present invention will be described in order.
  • R 1 is an alkyl group having 1 to 6 carbon atoms.
  • an ethyl group is preferable in consideration of the usefulness and ease of use of the obtained biphenylbenzimidazole derivative.
  • R 2 is an alkyl group having 1 to 6 carbon atoms, a cilexetil group, or a medoxomil group.
  • R 2 is preferably an alkyl group having 1 to 6 carbon atoms, A methyl group or an ethyl group is particularly preferable.
  • the benzimidazole derivative represented by the formula (1) is a known compound and can be produced according to a known method.
  • R A is a cyano group or a 1-trityl-1H-tetrazol-5-yl group; X is a halogen atom. ) It is a biphenyl compound shown by these.
  • the biphenyl compound has the following formula (2 ′′)
  • X is a halogen atom.
  • cyanobiphenyl compound (Hereinafter also referred to as “cyanobiphenyl compound”).
  • the biphenyl compound has the following formula (2 ′) when R A is a 1-trityl-1H-tetrazol-5-yl group:
  • Tr is a triphenylmethyl group (that is, a trityl group).) (Hereinafter also referred to as “tetrazolylbiphenyl compound”).
  • the halogen atom X in the formula (2) is preferably a bromine atom or a chlorine atom, more preferably a bromine atom.
  • the biphenyl compound (2) is a known compound and can be produced according to a known method.
  • the amount of the biphenyl compound used is not particularly limited, but is preferably 0.8 to 5 moles, preferably 0.9 to 2.0 moles per mole of the benzimidazole derivative. More preferably, the molar amount is 1.0 to 1.5 mol. According to the present invention, since the reaction between the reaction solvent and the biphenyl compound can be suppressed, the amount of the biphenyl compound used can be reduced.
  • the resulting product is a cyanobiphenylbenzimidazole derivative having a cyano group.
  • the cyanobiphenylbenzimidazole derivative is an intermediate of various sultan based drug substances, and once this intermediate is manufactured, this intermediate is manufactured with various sultan based drug substances. be able to. Therefore, its usefulness is high.
  • the product obtained is a biphenylbenzimidazole derivative having a tetrazolyl group protected with a trityl group.
  • side reaction Trityl candesartan cilexetil or candesartan cilexetil can be produced in a small number of steps and in a small number of steps.
  • the reaction between the raw material compounds is carried out in the presence of a base.
  • Making the reaction system in the presence of a base can be achieved by adding a base to the reaction system.
  • an inorganic base for example, an inorganic base containing an alkali metal, an organic base, or the like can be used without any limitation.
  • alkali metal carbonates such as potassium carbonate and sodium carbonate are preferred in consideration of reactivity, availability, and ease of subsequent processing.
  • potassium carbonate is preferable in order to obtain the target biphenylbenzimidazole derivative with high yield.
  • the amount of the base used is not particularly limited, but considering the reactivity, ease of treatment in the subsequent steps, etc., it is 0.5 to 10 mol with respect to 1 mol of the benzimidazole derivative. Preferably, the amount is 1.0 to 5.0 mol.
  • the usage-amount of the said base is based on the total number of moles, when multiple types of base are used.
  • the iodine catalyst shown by these is present in the reaction system.
  • I represents an iodine atom
  • N represents a nitrogen atom
  • R 6 is an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, and the plurality of R 6 may be the same group or different groups.
  • iodine catalysts in view of availability, tetramethylammonium iodide, tetraethylammonium iodide, tetra-n-butylammonium iodide, benzyltrimethylammonium iodide, or the like can be used. preferable. These iodine catalysts can be used alone or in a plurality of types. Among these, it is preferable to use tetra-n-butylammonium iodide in consideration of reactivity, ease of processing in the subsequent process, cost, and the like.
  • the amount of the iodine catalyst used is 0.1% with respect to 1 mol of the benzimidazole derivative in consideration of reactivity, ease of treatment in the subsequent step, and the like.
  • the amount is preferably 001 to 1.0 mol, more preferably 0.01 to 0.1 mol.
  • the usage-amount of the said iodine catalyst is based on the total number of moles, when multiple types of iodine catalysts are used.
  • reaction solvent (Branched alcohol)
  • Branched alcohol A feature of the present invention is that the reaction between the two raw material compounds is represented by the following formula (4) in the presence of the base and the iodine catalyst used as necessary.
  • each of R 3 , R 4 , and R 5 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an alkyloxyalkyl group having 2 to 12 carbon atoms.
  • R 3 , R 4 , and R 5 are groups in which two or more groups are not hydrogen atoms at the same time.
  • the branched alcohol represented by the formula (4) includes at least a group selected from an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, and an alkyloxyalkyl group having 2 to 12 carbon atoms.
  • groups other than hydrogen atoms in R 3 , R 4 and R 5 include methyl group, ethyl group, n-propyl group, An isopropyl group, n-butyl group, methoxymethyl group, ethoxymethyl group, n-butoxymethyl group and the like are preferable.
  • the alcohol (4) from the viewpoint of increasing the production rate of the biphenylbenzimidazole derivative, if the tetrazolylbiphenyl compound is used, from the viewpoint of further suppressing detritylation, the number of carbon atoms of 3 to 6 Secondary alcohols or tertiary alcohols are preferable, and secondary alcohols having 3 to 6 carbon atoms are particularly preferable.
  • isopropyl alcohol (2-propanol), 2-butanol, t-butanol, 2-pentanol, 3-pentanol, 1-methoxy-2-propanol, 1-ethoxy- 2-Propanol, 1-butoxy-2-propanol is preferably used.
  • isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol is more preferable
  • 2-butanol is a yield of biphenylbenzimidazole derivative and easy handling (easy to remove). In particular, it is preferable in terms of versatility and safety.
  • the following branched alcohol depending on the type of biphenyl compound.
  • a cyanobiphenyl compound it is more preferable to use isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol.
  • isopropyl alcohol or 2-butanol in consideration of the yield and the effect of suppressing isomers.
  • a tetrazolylbiphenyl compound when used, it is more preferable to use isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol.
  • 2-butanol, 3-pentanol, or t-butanol it is particularly preferable to use 2-butanol, 3-pentanol, or t-butanol in consideration of the high conversion rate of the benzimidazole derivative, the ether by-product, and the effect of suppressing isomers.
  • the use of 2-butanol, 3-pentanol, or t-butanol is considered to suppress the elimination reaction of the trityl group.
  • 2-butanol is used in consideration of the yield of biphenylbenzimidazole derivatives, ease of handling (easy to remove), versatility, safety, etc. It is preferable to do.
  • reaction solvent is a branched alcohol as described above, the amount of ether by-product that is a reaction product of the biphenyl compound and the reaction solvent can be suppressed. This is considered to be because the reactivity between the biphenyl compound and the branched alcohol is low and the production of ether by-products can be suppressed.
  • the reaction temperature is set to a relatively low value (near room temperature, for example, 10 to 30 ° C.), Can be remarkably suppressed.
  • the reaction temperature is set to a relatively low value (near room temperature, for example, 10 to 30 ° C.)
  • the reaction temperature is set to a relatively low value (near room temperature, for example, 10 to 30 ° C.)
  • the branched alcohol acts on one nitrogen atom to be reacted in the benzimidazole derivative (the 1st-position nitrogen atom in the following formula) by a hydrogen bond or the like, and as a result, a base easily acts on the nitrogen atom.
  • the biphenylbenzimidazole derivative which is aimed at with high selectivity (“high selectivity” means a high proportion of the biphenylbenzimidazole derivative produced and the biphenylbenzimidazole derivative in the isomer). Is estimated to be obtained. Although it depends on the type of branched alcohol used, it is presumed that the reason why the selectivity may be higher than that of linear alcohol is as follows. That is, it is considered that the oxygen atom of the branched alcohol having an electron density higher than the oxygen atom of the linear alcohol (the oxygen atom of the hydroxyl group) acts strongly on the hydrogen atom bonded to the nitrogen atom. This is presumed to be the cause of high selectivity. In particular, when the reaction temperature is relatively low, it is considered that the above-described action is remarkably exhibited. Such an effect becomes remarkable when a cyanobiphenyl compound is used.
  • reaction of the detrityl group in reaction of this invention can be suppressed.
  • the entire amount of the reaction solvent may be the branched alcohol, except for a solvent inevitably mixed in the reaction system.
  • the reaction solvent can also contain a polar solvent (excluding the branched alcohol).
  • the polar solvent used in combination with the branched alcohol is preferably a polar solvent having a relative dielectric constant of preferably 20 or more, more preferably 30 or more.
  • the upper limit of the relative dielectric constant is not particularly limited, but is 100.
  • the polar solvent may be an aprotic polar solvent or a polar solvent containing a hetero atom. Among them, it is preferable to use a polar solvent containing a hetero atom such as a nitrogen atom, a sulfur atom, or an oxygen atom.
  • Suitable polar solvents include acetonitrile (dielectric constant 37), N, N-dimethylformamide (dielectric constant 38), N, N-dimethylacetamide (dielectric constant 38), N-methyl- Examples include 2-pyrrolidone (relative permittivity: 32.2) and dimethyl sulfoxide (relative permittivity: 47).
  • a polar solvent in order to suppress the generation of ether by-products, achieve high selectivity, shorten the reaction time, and facilitate post-treatment, among the polar solvents, N, N-dimethylformamide, N, N-dimethylacetamide is preferably used.
  • polar solvents can be used singly or as a mixture of plural kinds.
  • the polar solvent when a polar solvent is used, in order to suppress the generation of ether by-products and achieve high selectivity, when the branched alcohol is 1 ml, the polar solvent is 0.01 to 1 ml. It is preferably 0.05 to 0.5 ml, more preferably 0.1 to 0.3 ml. In addition, when using multiple types of polar solvent, the total amount of this multiple types of polar solvent should just satisfy the said range.
  • the amount of the reaction solvent used is not particularly limited, and an amount that can sufficiently contact the benzimidazole derivative and the biphenyl compound in the reaction system may be used.
  • the reaction solvent is preferably used in an amount such that the reaction solvent is 0.5 to 100 ml with respect to 1 g of the benzimidazole derivative, and more preferably 1 to 20 ml. This amount is the amount of the reaction solvent at 23 ° C.
  • the amount of the reaction solvent may be such that the total amount of the branched alcohol and the polar solvent satisfies the above range.
  • the total amount of them should just satisfy the said range.
  • the benzimidazole derivative and the biphenyl compound may be contacted in the reaction solvent in the presence of a base. Therefore, it is preferable to stir and mix the base, the benzimidazole derivative, and the cyanobiphenyl compound in the reaction solvent.
  • the procedure for introducing each component into the reaction system is not particularly limited.
  • the base diluted with the reaction solvent as necessary, the iodine catalyst used as necessary, the benzimidazole derivative, and the biphenyl compound can be mixed with stirring while being simultaneously introduced into the reaction system.
  • one raw material compound diluted with a reaction solvent is first introduced into the reaction system and stirred and mixed, and if necessary, the other raw material compound diluted with a reaction solvent is added to the reaction system.
  • the method of adding can also be employ
  • the base and the iodine catalyst used as necessary can be introduced into the reaction system together with the one raw material compound in advance.
  • the raw material compound can be added to the reaction system simultaneously with the addition of the other raw material compound, or can be added separately to the reaction system after the other raw material compound is added.
  • the reaction temperature is not particularly limited. In order to suppress the generation of ether by-products, achieve high selectivity, and obtain a biphenylbenzimidazole derivative in a high yield, ⁇ 30 to 150 It is preferable to set it as ° C. Among them, the reaction temperature is preferably 0 to 100 ° C., more preferably 5 to 70 ° C., in order to further suppress the generation of ether by-products and to achieve higher selectivity and higher yield. More preferably, the temperature is 10 to 60 ° C. Further, the reaction temperature is preferably 25 to 60 ° C.
  • reaction time is not particularly limited, and may be appropriately determined while confirming the consumption state of the raw material compound or the amount of the biphenylbenzimidazole derivative to be generated. Specifically, 0.5 to 72 hours is sufficient, and may be about 1 to 24 hours.
  • the atmosphere in the reaction system is not particularly limited, and the reaction can be performed in any atmosphere such as an air atmosphere or an inert gas atmosphere.
  • the pressure in the reaction system is not particularly limited, and the reaction of the present invention may be carried out in any state under atmospheric pressure, reduced pressure, or increased pressure.
  • the target biphenylbenzimidazole derivative can be produced by carrying out the reaction according to the above method.
  • the method for taking out the biphenylbenzimidazole derivative from the reaction system is not particularly limited, and a known method can be adopted.
  • a method of crystallizing the biphenylbenzimidazole derivative by adding water as a poor solvent into the system, extraction with a solvent, washing, or distillation of the reaction solvent, and then recrystallization of the obtained solid content A method etc. can be adopted.
  • the purity of the obtained biphenylbenzimidazole derivative can be increased by slurry purification, recrystallization, column purification, or the like.
  • the biphenylbenzimidazole derivative represented by can be increased.
  • the biphenylbenzimidazole derivative may be referred to as “cyanobiphenylbenzimidazole derivative” when R A is a cyano group, and when R A is a 1-trityl-1H-tetrazol-5-yl group. May be described as “candesartan intermediate”.
  • the branched alcohol when the branched alcohol is not used, specifically, when a linear alcohol such as methanol or ethanol is used as a reaction solvent, the linear alcohol and the biphenyl compound It was found that a large amount of ether by-product was produced. Since the branched alcohol used in the present invention is bulkier than the straight chain alcohol, it is considered that the reaction with the biphenyl compound is difficult to proceed.
  • a linear alcohol such as methanol or ethanol
  • the production of the ether by-product can be reduced and the production rate of the isomer can be suppressed.
  • the rate can be improved.
  • the cyanobiphenyl compound is used as the biphenyl compound and the sultan drug substance such as candesartan or azilsartan is produced from the obtained cyanobiphenylbenzimidazole derivative, impurities can be efficiently reduced.
  • R A in the biphenylbenzimidazole derivative becomes a cyano group, and the cyano group can be substituted with various groups depending on the target drug substance. Therefore, when the obtained compound is a cyanobiphenylbenzimidazole derivative, the obtained compound can be used as an intermediate of candesartan or azilsartan, so that the usefulness is increased.
  • the biphenylbenzimidazole derivative is represented by the following formula (3 ′)
  • Et is an ethyl group
  • Tr is a triphenylmethyl group.
  • a candesartan intermediate is prepared by the method for producing a biphenylbenzimidazole derivative of the present invention, and then the obtained candesartan intermediate By hydrolyzing the ester group, the following formula (6)
  • Et is an ethyl group
  • Tr is a triphenylmethyl group.
  • the trityl candesartan shown by this can be manufactured. Hydrolysis can be carried out by a known method.
  • Et is an ethyl group and a Tr triphenylmethyl group.
  • the trityl candesartan cilexetil shown by can be manufactured. Introduction of a cilexetil group can be carried out by a known method.
  • the biphenylbenzimidazole derivative or the candesartan intermediate may be used as the biphenylbenzimidazole derivative or the candesartan intermediate by the method for producing a biphenylbenzimidazole derivative of the present invention.
  • the represented trityl candesartan cilexetil can be produced.
  • a candesartan cilexetil represented by the following formula (8) is produced from the trityl candesartan cilexetil by a detritylation reaction. Can do.
  • the detritylation reaction (i.e. deprotection reaction) can be carried out in a known manner, by using water, acid, alcohol or alkali, in particular by using safe water and / or alcohol. Can be implemented.
  • biphenyl compound is the tetrazolyl biphenyl compound, according to the present invention, a candesartan intermediate that is easy to perform a deprotection reaction is produced, and finally candesartan cilexetil is also an easy method. Can be manufactured.
  • HPLC high performance liquid chromatography
  • Example 3 The same operation as in Example 1 was performed except that the reaction temperature was 40 ° C.
  • Example 6 The same operation as in Example 1 was carried out except that isopropyl alcohol (10 mL) was used instead of 2-butanol as the reaction solvent and the reaction temperature was 40 ° C.
  • Example 7 The same operation as in Example 1 was performed except that 1-ethoxy-2-propanol (10 mL) was used instead of 2-butanol as a reaction solvent.
  • Example 8 The same operation as in Example 1 was carried out except that 1-butoxy-2-propanol (10 mL) was used instead of 2-butanol as the reaction solvent.
  • Example 9 The same operation as in Example 1 was performed except that 2-pentanol (10 mL) was used instead of 2-butanol as a reaction solvent and the reaction temperature was 40 ° C.
  • Example 10 The reaction was conducted in the same manner as in Example 1 except that 3-pentanol (10 mL) was used instead of 2-butanol as the reaction solvent and the reaction temperature was 40 ° C.
  • Example 11 The reaction was conducted in the same manner as in Example 1 except that t-butanol (10 mL) was used instead of 2-butanol as a reaction solvent and the reaction temperature was 40 ° C.
  • Example 1 The same operation as in Example 1 was performed except that methanol (10 mL) was used instead of 2-butanol as a reaction solvent.
  • Example 2 The same operation as in Example 1 was performed, except that ethanol (10 mL) was used instead of 2-butanol as a reaction solvent.
  • Example 3 The same operation as in Example 1 was carried out except that N, N-dimethylformamide (10 mL) was used instead of 2-butanol as the reaction solvent.
  • Comparative Example 4 The same operation as in Comparative Example 3 was performed except that the reaction temperature was 40 ° C.
  • Table 1 shows the results of Examples 1 to 11 and Comparative Examples 1 to 5 described above.
  • the use of the reaction solvent containing the branched alcohol could suppress the formation of the ether by-product.
  • the reaction solvent containing the branched alcohol by using the reaction solvent containing the branched alcohol and setting the reaction temperature to 10 to 30 ° C., the production ratio of the isomer could be suppressed (Example 1).
  • the reaction temperature is set to 40 to 60 ° C. or a reaction solvent containing a polar solvent is used, the conversion of the benzimidazole derivative can be increased while suppressing the by-production of the isomer.
  • the yield of the target product could be increased (Examples 2 and 4).
  • Example 13 The same operation as in Example 12 was performed, except that 2-butanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 14 The same operation as in Example 12 was performed, except that 2-butanol (16 mL) and N, N-dimethylacetamide (4 mL) were used in place of isopropyl alcohol as the reaction solvent.
  • Example 15 The same operation as in Example 12 was performed, except that 2-pentanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 16 The same operation as in Example 12 was performed, except that 3-pentanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 17 The same operation as in Example 12 was performed, except that t-butanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 18 The same operation as in Example 12 was performed, except that 1-methoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 19 The same operation as in Example 12 was performed, except that 1-ethoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Example 20 The same operation as in Example 12 was performed, except that 1-butoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.
  • Table 2 shows the results of Examples 12 to 20 and Comparative Examples 6 to 9 described above.
  • Example 21 2-Ethoxy-1- [2 ′-[1-triphenylmethyl-1H-tetrazol-5-yl] biphenyl-4-yl] -1H-benzimidazole-7-carboxylic acid methyl ester obtained in Example 13 (Candesartan intermediate) 1 g (1.43 mmol) was stirred at 70 ° C. for 3 hours in a mixed solvent of 6 ml of 1N NaOH aqueous solution and 20 ml of ethanol. After cooling the reaction solution, ice water containing 6 ml of 1N HCl was gradually added to the reaction solution. Extraction with methylene chloride, drying, filtration and concentration were performed to obtain 0.89 g (1.30 mmol) of a crude product of trityl candesartan (compound represented by formula (6)) as a solid.

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  • Plural Heterocyclic Compounds (AREA)
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Abstract

Le problème selon la présente invention est de procurer un procédé de production apte à inhiber la production de sous-produits, etc. et d'améliorer le rendement d'un dérivé de biphényl benzimidazole qui est le produit voulu. La solution de l'invention porte sur un procédé de production d'un dérivé de biphényle benzimidazole représenté par la réaction, en présence d'une base, d'un dérivé de benzimidazole représenté par (R1 représente un groupe alkyle en C1-6, et R2 représente un groupe alkyle en C1-6, un groupe cilexétil ou un groupe médoxomil) avec un composé biphényle représenté par (Ra représente un groupe cyano ou un groupe 1-trityl-1 H-tétrazole-5-yle, et X représente un atome d'halogène), la réaction étant effectuée dans un solvant de réaction comportant un alcool ramifié représenté par (R3, R4, et R5 représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6, ou analogue. Cependant, au moins deux groupes parmi R3-R5 ne peuvent pas être simultanément un atome d'hydrogène).
PCT/JP2017/019877 2016-05-31 2017-05-29 Procédé de production d'un dérivé de biphényle benzimidazole Ceased WO2017209035A1 (fr)

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SEKI, M.: "Efficient Catalytic System for Ru- Catalyzed C-H Arylation and Application to a Practical Synthesis of a Pharmaceutical", ACS CATAL., vol. 4, 2014, pages 4047 - 4050, XP055443505 *
SHI, X-F. ET AL.: "Synthesis of candesartan cilexetil", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 4, 2012, pages 290 - 293 *

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