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WO2018008219A1 - Intermédiaire d'azilsartan, azilsartan, procédé de production d'un intermédiaire d'azilsartan et procédé de production d'azilsartan - Google Patents

Intermédiaire d'azilsartan, azilsartan, procédé de production d'un intermédiaire d'azilsartan et procédé de production d'azilsartan Download PDF

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Publication number
WO2018008219A1
WO2018008219A1 PCT/JP2017/014529 JP2017014529W WO2018008219A1 WO 2018008219 A1 WO2018008219 A1 WO 2018008219A1 JP 2017014529 W JP2017014529 W JP 2017014529W WO 2018008219 A1 WO2018008219 A1 WO 2018008219A1
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Prior art keywords
azilsartan
methyl
biphenyl
ethoxy
benzimidazole
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English (en)
Japanese (ja)
Inventor
森　博志
吉貴 清家
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Tokuyama Corp
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Tokuyama Corp
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Priority claimed from JP2016133605A external-priority patent/JP6676487B2/ja
Priority claimed from JP2016138165A external-priority patent/JP6676491B2/ja
Priority claimed from JP2016219237A external-priority patent/JP2018076258A/ja
Priority claimed from JP2016232241A external-priority patent/JP6856365B2/ja
Application filed by Tokuyama Corp filed Critical Tokuyama Corp
Priority to CN201780042206.2A priority Critical patent/CN109415327A/zh
Publication of WO2018008219A1 publication Critical patent/WO2018008219A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an azilsartan intermediate, azilsartan, and methods for producing them. More specifically, an alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate, which is an azilsartan intermediate, and Alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- Carboxylate; 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] which is azilsartan Methyl] benzimidazole-7-carboxylic acid and methods for producing them.
  • Azilsartan (also known as: 1-[[2 '-(4,5-dihydro-5-oxo-1,2,4- oxadiazol-3-yl) [1,1'-biphenyl-4- [Il] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid) is a very useful compound as a therapeutic agent showing an excellent effect as an angiotensin II receptor antagonist (Patent Document 1).
  • This azilsartan is synthesized by the following manufacturing method.
  • an alkyl 1-[(2′-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate represented by the above formula (1) (hereinafter simply referred to as “nitrile compound”)
  • the alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4 represented by the above formula (2) is reacted with hydroxylamine and / or hydroxylamine acid salt.
  • -Yl] methyl] -1H-benzimidazole-7-carboxylate hereinafter sometimes simply referred to as “amidoxime compound”).
  • the amidoxime compound is used as it is in the cyclization reaction, or an alkyl 2-ethoxy-1-[[2 ′-(alkyloxy) represented by the above formula (3) in which the hydroxyl group of the amidoxime compound is protected with an ester protecting group.
  • the azilsartan alkyl ester represented by the formula (5) is produced by hydrolyzing the azilsartan alkyl ester (see, for example, Patent Documents 1 to 3 and Non-Patent Document 1).
  • Drug substances like azilsartan are desired to reduce impurities.
  • an impurity different from the target product may be generated in each step. Since this impurity has a structure similar to that of the target product, purification or the like becomes very difficult when the amount thereof increases. Therefore, in the case of producing a drug substance, it is desired to reduce impurities even in the production of an intermediate.
  • a desethyl form of the nitrile compound represented by (hereinafter, sometimes simply referred to as “nitrile desethyl form”), and the production ratio of the amidoxime compound is small.
  • Non-Patent Document 1 hydroxylamine hydrochloride is used, and the reaction is carried out in a reaction solvent of dimethyl sulfoxide in the presence of an organic base such as triethylamine as a base. According to studies by the present inventors, in this method, the production rate of the amidoxime compound is increased. However, at the same time, the same amount as the amidoxime compound (8)
  • a desethyl derivative of the amidoxime compound represented by the formula (hereinafter sometimes simply referred to as “amidoxime desethyl derivative”), and the following formula (10)
  • amide desethyl form represented by the formula (hereinafter, sometimes simply referred to as “amide desethyl form”) tends to increase.
  • the purity of the amidoxime compound, the purity of other compounds, and the content ratio of impurities are the area% of each peak measured under the measurement conditions of high performance liquid chromatography (HPLC) described in the examples. .
  • a first object of the present invention is to provide a method for producing the amidoxime compound, which can obtain the amidoxime compound with high yield and high purity by a simple operation. Furthermore, it is providing the method of manufacturing a highly purified azilsartan using the said amidoxime compound manufactured by this method.
  • Non-Patent Document 1 an ester protecting group-containing compound in which R 2 is a 2-ethylhexyl group is used as a reaction solvent with xylene at a reflux temperature (the reflux temperature of the reaction solution; about 130 ° C.).
  • An azilsartan methyl ester is produced by a chemical reaction. According to this method, azilsartan methyl ester can be obtained in a relatively short reaction time (yield: 52%).
  • Non-Patent Document 1 the structure is not clear, but in the analysis result of the liquid chromatograph mass spectrometer (LC-MASS), the azilsartan methyl ester It was found that impurities having a molecular weight obtained by adding 10 to the molecular weight increased.
  • LC-MASS liquid chromatograph mass spectrometer
  • Patent Document 1 an ester protecting group-containing compound in which R 2 is an ethyl group is used as a reaction solvent, xylene is used, and the cyclization reaction is performed in the xylene at the reflux temperature (the reflux temperature of the reaction solution; about 130 ° C.). To produce azilsartan methyl ester. However, it has been found that this method also increases the impurities. Furthermore, in the method described in Patent Document 1, the yield is as low as about 23%, and there is room for improvement.
  • Patent Document 1 also discloses a method of performing a cyclization reaction in ethyl acetate in the presence of a base (potassium carbonate, diazabicycloundecene).
  • a base potassium carbonate, diazabicycloundecene
  • azilsartan methyl ester is precipitated during the reaction. Therefore, azilsartan methyl ester is obtained as a solid containing the base. As a result, there is room for improvement in that the purification process becomes complicated.
  • the second object of the present invention is to provide a method for producing a high yield and high purity azilsartan alkyl ester.
  • an object of the present invention is to provide a method for producing an azilsartan alkyl ester that can facilitate a purification step, which is a subsequent step.
  • it is to provide a method for producing high-purity azilsartan using the azilsartan alkyl ester produced by the method.
  • Patent Document 1 describes the following method. First, a cyclization reaction is carried out in xylene for an ester protecting group-containing compound in which R 1 is a methyl group and R 2 is an ethyl group to synthesize azilsartan methyl ester. Next, after adding ethyl acetate to the reaction solution, washing and drying with water, xylene is distilled off, the residue is purified by silica gel chromatography, and the resulting crude crystals are recrystallized from ethyl acetate and isopropyl ether.
  • Non-Patent Document 1 describes the following method. First, a compound containing an ester protecting group in which R 1 is a methyl group and R 2 is a 2-ethylhexyl group is subjected to a cyclization reaction in xylene to synthesize an azilsartan methyl ester. Next, xylene is distilled off and recrystallization is performed using ethyl acetate.
  • the melting point of conventionally known azilsartan methyl ester is as high as 190 to 200 ° C. Therefore, if an azilsartan methyl ester having a lower melting point can be produced, it is considered that it is easily dissolved in a solvent and does not increase unnecessary impurities when used as an azilsartan. Therefore, development of azilsartan methyl ester having a novel crystal form has been demanded.
  • a third object of the present invention is to provide a method for producing a high-purity azilsartan alkyl ester.
  • it is to provide a novel crystalline form of azilsartan methyl ester having a low melting point.
  • high-purity azilsartan alkyl ester produced by the above method and / or high-purity azilsartan methyl ester having a novel crystalline form with high purity is produced. It is to provide a way to do.
  • the inventors of the present invention have made extensive studies to solve the above problems (1) to (3). And when manufacturing the said amidoxime compound, in the prior art, the reason for using an aprotic polar solvent like dimethyl sulfoxide was estimated as follows. That is, when a protic solvent or the like is used, the —OR (R; alkyl group having 1 to 4 carbon atoms) and —OEt (Et; ethyl group) moieties in the nitrile compound represented by the formula (1) are transesterified. It was thought that the reaction might become more complicated.
  • the compound has high solubility in the ester protecting group-containing compound and the azilsartan alkyl ester, and the reaction is performed without decomposing the ester protecting group-containing compound and the azilsartan alkyl ester in the cyclization reaction.
  • the conditions that can be promoted were examined. As a result, it was found that the above problem can be solved by carrying out the cyclization reaction in a specific reaction solvent, that is, a reaction solvent containing an alcohol having 1 to 8 carbon atoms, and the second invention has been completed. .
  • R 1 is an alkyl group having 1 to 4 carbon atoms
  • a nitrile compound represented by Hydroxylamine and / or hydroxylamine acid salt By reacting in a reaction solvent containing an alcohol having 2 to 7 carbon atoms, following formula (2)
  • the reaction is preferably performed in the presence of a base.
  • a base By performing the reaction in the presence of a base, the by-production of the amide form and the amide desethyl form can be further suppressed.
  • the base in order to suppress the by-product of the amide form and the amide desethyl form more highly and improve operability, the base preferably contains an organic base.
  • the blending amount is preferably 0.01 to 0.5 mol with respect to 1 mol of the nitrile compound represented by the formula (1).
  • the alcohol in order to produce the high-purity amidoxime compound and to further improve the operability, is a linear or branched alcohol having 3 to 7 carbon atoms. There are preferred. Furthermore, it is preferable that hydroxyamine is used and the reaction solvent contains water.
  • the amidoxime compound obtained by the method of the present invention has high purity and few impurities. Therefore, the amidoxime compound obtained by the method of the present invention can be suitably used for the production of the azilsartan alkyl ester represented by the formula (4) and the azilsartan represented by the formula (5).
  • R 1 has the same meaning as in formula (3).
  • the cyclization reaction is preferably performed at 50 ° C. or higher and the reflux temperature of the reaction solution or lower.
  • the reflux temperature is substantially the same as the temperature at which the reaction solvent refluxes.
  • the “reflux temperature of the reaction solution” is slightly different depending on the concentration of by-product R 2 —OH (alcohol having R 2 group), dissolved azilsartan alkyl ester, etc. This is because there is a difference with temperature.
  • the reaction solution refers to a solution containing R 2 —OH produced as a by-product by dissolving an ester group-containing compound and / or an azilsartan alkyl ester in a reaction solvent.
  • a reaction solution contains a base as a matter of course.
  • the alcohol is preferably a linear or branched alcohol having 3 to 8 carbon atoms.
  • this alcohol not only a high yield and high purity azilsartan alkyl ester can be obtained, but also the azilsartan alkyl ester can be easily crystallized in the reaction solvent after completion of the reaction. As a result, the post-processing process can be facilitated.
  • the cyclization reaction is preferably performed in the presence of a base.
  • the amount of the base used is preferably 0.01 to 5 mol with respect to 1 mol of the ester protecting group-containing compound represented by the formula (3).
  • the base is preferably an organic base.
  • the method of manufacturing the azilsartan shown by this is included. According to the present invention, a highly pure azilsartan alkyl ester can be produced, so that a highly purified azilsartan can be obtained.
  • the third aspect of the present invention provides following formula (4)
  • R 1 is an alkyl group
  • the third aspect of the present invention relates to the above formula (4), wherein R 1 is a methyl group, that is, methyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo- 1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as “azirsartan methyl ester”) Especially effective.
  • the azilsartan methyl ester can be in a quasicrystalline state having a portion with a low melting point.
  • the azilsartan methyl ester is preferably a compound having at least a melting point in a temperature range of 150 to 165 ° C. and a temperature range of 185 to 195 ° C.
  • the third present invention includes a method for producing azilsartan by hydrolyzing azilsartan alkyl ester and / or azilsartan methyl ester produced by this method. By using these as raw materials, azilsartan with higher purity can be produced.
  • the first to third methods for producing azilsartan of the present invention include a method in which a step of removing azilsartan dimers contained as impurities using activated carbon is added.
  • the first to third methods for producing azilsartan of the present invention include a step of precipitating azilsartan by adding a solvent of ketones or esters to a solution obtained by dissolving azilsartan in dimethylformamide. The manufacturing method to which is added.
  • the present invention provides the amidoxime compound from the nitrile compound by the production method of the first invention, Next, the ester protecting group-containing compound is obtained from the amidoxime compound, By the production method of the second invention, the azilsartan alkyl ester is obtained from the ester protecting group-containing compound, The manufacturing method of obtaining the said azilsartan from the said azilsartan alkyl ester by the manufacturing method of 3rd this invention is included.
  • an amidoxime compound with high yield and high purity can be obtained by a simpler operation.
  • the amidoxime compound obtained in the present invention to produce an azilsartan alkyl ester and azilsartan, these can also be made highly pure.
  • the second method of the present invention it is possible to obtain an azilsartan alkyl ester having a high yield and a high purity by a simpler operation.
  • high-purity azilsartan can be obtained by hydrolyzing the azilsartan alkyl ester obtained in the present invention to produce azilsartan.
  • the operability can also be improved.
  • a high-purity azilsartan alkyl ester particularly a high-purity azilsartan methyl ester
  • high-purity azilsartan can be obtained by hydrolyzing the azilsartan alkyl ester and / or azilsartan methyl ester obtained in the present invention to produce azilsartan.
  • the azilsartan methyl ester obtained by the method of the present invention can be a quasicrystal having a portion having a low melting point. Since these methods can increase the purity of azilsartan used as a drug substance, which is finally obtained, its industrial utility value is high.
  • Example 2 is an X-ray diffraction chart of a novel crystal of azilsartan methyl ester of the present invention produced in Example 10.
  • 6 is an X-ray diffraction chart of a conventional azilsartan methyl ester crystal produced in Comparative Example 4.
  • 19 is an X-ray diffraction chart of a novel crystal (quasicrystal) of azilsartan methyl ester of the present invention produced in Example 18.
  • 6 is an X-ray diffraction chart of a conventional azilsartan methyl ester crystal produced in Comparative Example 5.
  • 19 is a DSC chart of a novel crystal (quasicrystal) of azilsartan methyl ester of the present invention produced in Example 18.
  • 10 is a DSC chart of conventional azilsartan methyl ester crystals produced in Comparative Example 5.
  • 4 is an X-ray diffraction chart of an azilsartan M-type crystal of the present invention produced in Example 33.
  • the nitrile compound represented by the formula (1) is not particularly limited, and can be produced by a known method. Specifically, acetic acid is added to a method described in Patent Document 1, that is, a solution of alkyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl) methyl] amino] benzoate in ethyl orthocarbonate. It can manufacture by making it react at 80 degreeC for 1 hour stirring (refer Example 1b of patent document 1).
  • the amidoxime compound is produced by reacting the nitrile part of the nitrile compound with hydroxylamine and / or hydroxylamine acid salt.
  • hydroxylamine and / or hydroxylamine salt to be used is not particularly limited, and commercially available products can be used. It should be noted that “and / or” naturally refers to hydroxylamine alone, hydroxylamine acid salt alone, or a mixture of hydroxylamine and hydroxylamine acid salt. Hereinafter, when these are collectively referred to, they may be referred to as hydroxylamines.
  • hydroxylamine salt examples include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, hydroxylamine oxalate and the like. These hydroxylamine salts can also be used as hydroxylamine after neutralizing with a base.
  • the amount of hydroxylamine and / or hydroxylamine salt to be used is not particularly limited, but is preferably 1 to 10 mol, more preferably 2 to 7 mol, relative to 1 mol of the nitrile compound. It is preferable that
  • hydroxylamine and / or hydroxylamine acid salt it is preferable to use hydroxylamine in order to reduce the nitrile desethyl body and the amide body and to increase the purity of the obtained amidoxime compound.
  • hydroxylamine it is preferable to use an aqueous hydroxylamine solution, for example, an aqueous solution having a hydroxylamine concentration of 30 to 50% by mass from the viewpoint of easy availability.
  • the advantage of using hydroxylamine is not clear. However, the present inventors believe that the purity of the amidoxime compound can be increased because the reaction can proceed under an appropriate pH condition in this reaction.
  • the reaction solvent contains at least an alcohol having 2 to 7 carbon atoms and water.
  • the reaction solvent of the present invention may contain this water.
  • reaction solvent a reaction solvent containing an alcohol having 2 to 7 carbon atoms is used.
  • the amount of by-products of the amide and desethyl compounds can be reduced, and the amidoxime compound with high purity can be produced.
  • alcohols having 2 to 7 carbon atoms include ethanol, 1-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 3- Methyl-1-butanol, 1-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-methyl-2-pentanol, 2,4-dimethyl-3-pentanol, 3- Examples include ethyl-3-pentanol.
  • linear or branched alcohols having 3 to 7 carbon atoms are preferable from the viewpoints of yield and purity of the obtained amidoxime compound, the ratio of impurities contained therein, and finally removal of the reaction solvent.
  • 1-propanol, isopropanol, 1-butanol and 2-butanol are preferable, and 1-propanol and 1-butanol are particularly preferable.
  • the alcohols exemplified above can be used singly or in a mixture of two or more. When used as a mixture, the amount used is based on the total amount of the mixture.
  • the reaction solvent may contain other solvents as long as it contains an alcohol having 2 to 7 carbon atoms.
  • water in the case of using a hydroxylamine aqueous solution, water to be newly added, and other solvents compatible with alcohol having 2 to 7 carbon atoms can be added.
  • the content of the other solvent is preferably less than 50% by mass and more preferably 30% by mass or less in the total amount of the reaction solvent of 100% by mass.
  • Preferred (naturally the balance of the reaction solvent is an alcohol having 2 to 7 carbon atoms).
  • the total amount of the reaction solvent may be an alcohol having 2 to 7 carbon atoms.
  • the alcohol having 2 to 7 carbon atoms is used. It is preferable that the alcohol is 70 to 99% by mass and the water is 1 to 30% by mass.
  • the amount of reaction solvent used is not particularly limited, and the raw material compound can be sufficiently mixed during the reaction, and the raw material compound and the amidoxime compound to be produced are sufficiently dissolved. Use as much as you can. Among them, in order to make it easy to take out the obtained amidoxime compound as crystals, it is preferable to use 5 to 50 ml of reaction solvent, and more preferably 6 to 30 ml, with respect to 1 g of the nitrile compound. In addition, the usage-amount of this reaction solvent is a volume in 23 degreeC.
  • reaction method In the present invention, the reaction can be carried out by contacting the nitrile compound with hydroxylamines in a reaction solvent containing an alcohol having 2 to 7 carbon atoms. Therefore, what is necessary is just to stir and mix the said nitrile compound and hydroxylamines in this reaction solvent, and to make both which are raw material compounds contact.
  • base In the method of this invention, when making both the raw material compounds contact (react), it can also implement in presence of a base. By using a base, the purity of the amidoxime compound can be further increased, and in particular, the amount of by-products of the amide body and the amide desethyl body can be suppressed.
  • a known base can be used as the base to be used. Specifically, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.
  • Inorganic bases and methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N-dimethylaminopyridine, diazabicycloundecene, N-methylmorpholine Organic bases such as can be used. These can be used singly or a plurality of types can be used simultaneously. When a plurality of types are used at the same time, the reference blending amount is based on the total amount of the plurality of types.
  • an organic base particularly when it is desired to suppress the amount of the amide form and by-product of the amide desethyl form.
  • an organic base By using an organic base, the removal of the organic base is facilitated.
  • triethylamine, pyridine, and diisopropylethylamine are preferably used in consideration of industrial production.
  • the amount of base used is not particularly limited, and may be a normal amount of catalyst.
  • the amount of the organic base used is preferably 0.01 to 0.5 mol with respect to 1 mol of the nitrile compound represented by the formula (1).
  • the amount of the organic base used is 0.1 to 1 mol with respect to 1 mol of the nitrile compound represented by the formula (1).
  • the amount is preferably 0.5 mol, particularly preferably 0.2 to 0.5 mol.
  • reaction conditions In the present invention, other reaction conditions are not particularly limited, but the reaction is preferably carried out under the following conditions.
  • the procedure for introducing each component into the reaction vessel when mixing the raw material compound, the reaction solvent, and the base compounded as necessary in the reaction vessel is not particularly limited. Specifically, a method of simultaneously introducing a raw material compound, a reaction solvent, and a base to be blended as necessary into a reaction vessel can be employed. Also, one raw material compound and a reaction solvent are previously introduced into a reaction vessel, and then the other raw material compound (may be diluted with a reaction solvent if necessary), and a base compounded as necessary (Which may be diluted with a reaction solvent) can also be introduced into the reaction vessel. At this time, the raw material compound to be added later may be divided and introduced several times.
  • the nitrile compound and the reaction solvent are charged into a reaction vessel. Subsequently, the base mix
  • the reaction temperature (the temperature of the reaction solution after all the components are mixed) is not particularly limited, but it is preferable to carry out the reaction at 50 ° C. or higher and the reflux temperature of the reaction solution or lower. Since the reflux temperature of the reaction solution varies depending on the type of reaction solvent used, the concentration of the raw material compound, and the like, it cannot be generally limited. However, in order to suppress decomposition of the amidoxime compound, the temperature of the reaction solution is preferably 50 to 100 ° C. or less, and preferably 60 to 95 ° C.
  • the reaction time (the time after all components are mixed) is not particularly limited, and may be determined while confirming the consumption ratio of the nitrile compound, the formation ratio of the amidoxime compound obtained, and the like. .
  • the amidoxime compound may be decomposed if the reaction time is too long, it is usually preferable to set the reaction time to 1 to 20 hours.
  • the atmosphere during the reaction is not particularly limited, and the reaction can be performed in the presence of air or in the presence of an inert gas. Further, the reaction can be carried out under reduced pressure, increased pressure, or atmospheric pressure. Among these, in order to improve operability, it is preferable to perform the reaction in the presence of air and atmospheric pressure.
  • the amidoxime compound can be produced.
  • the amidoxime compound produced in the reaction solution is preferably taken out by cooling the reaction solution or distilling off the reaction solvent for crystallization.
  • the temperature of the reaction solution is 50 ° C. or higher and lower than the reflux temperature of the reaction solution, it is preferably cooled to a temperature of 30 ° C. or lower, more preferably 10 to 30 ° C. It is preferable to precipitate crystals of the amidoxime compound.
  • it is preferable to set the cooling rate when the reaction temperature is 30 ° C. or less to 5 to 50 ° C./hour.
  • the precipitated amidoxime compound crystals can be treated by a known method. Usually, it is preferable to take out the crystals by filtration, wash and dry. In order to obtain a hydroxylamidino compound with higher purity, recrystallization may be performed with a reaction solvent.
  • the amidoxime compound obtained has a purity of 90.0 to 98.0%, amide 0.1 to 3.0%, nitrile desethyl 0.0 (undetected) to 0.5 %, The amidoxime desethyl compound 0.1 to 1.0%, and the amido desethyl compound 0.05 to 1.0%.
  • the purity is preferably 94.0 to 98.0%, the amide body 0.1 to 2.0%, the nitrile desethyl body 0.0 (undetected) to 0.1%
  • the amidoxime desethyl compound of 0.1 to 1.0% and the amido desethyl compound of 0.05 to 0.5% can be used.
  • the purity is 94.0 to 98.0%, the amide compound 0.1 to 1.0%, the nitrile desethyl compound 0.0 (undetected) to 0.1%, the amidoxime desethyl compound 0 .1 to 1.0%, and high purity of the above amidedesethyl compound 0.05 to 0.5%.
  • the purity of the amidoxime compound, the amide body, the nitrile desethyl body, the amidoxime desethyl body, and the amiddesethyl body ratio may include other components, the total is not necessarily 100%. It will not be.
  • amidoxime compound can be suitably used as a starting material for azilsartan alkyl ester and azilsartan.
  • Org. Process As described in Res. Dev 2013, 17, cyclization directly from the amidoxime compound by reaction in a reaction solvent containing 1,1′-carbonylimidazole, diazabicycloundecene, and dimethyl sulfoxide.
  • the reaction can be carried out and the azilsartan alkyl ester can be produced.
  • the amidoxime compound and an alkyl chloroformate (the alkyl group is a protecting group for a hydroxyl group, specifically, a 2-ethylhexyl group or an ethyl group) are combined with an organic base ( (Pyridine or triethylamine) in the presence of dimethylformamide, tetrahydrofuran / dichloromethane solvent, to give the following formula (3)
  • R 2 is an alkyl group that protects a hydroxyl group, specifically a 2-ethylhexyl group or an ethyl group
  • R 2 is an alkyl group that protects a hydroxyl group, specifically a 2-ethylhexyl group or an ethyl group
  • R 2 is an alkyl group that protects a hydroxyl group, specifically a 2-ethylhexyl group or an ethyl group
  • the obtained azilsartan alkyl ester is not particularly limited.
  • Process. Purification, etc. may be carried out by the methods described in Res. Dev 2013, 17, Non-Patent Document 1, and Patent Document 1.
  • Specific examples include a method of recrystallization from acetone, ethyl acetate, ethyl acetate / isopropyl ether, chloroform / ethyl acetate.
  • a method of recrystallization from acetone In order to further increase the purity of the resulting azilsartan alkyl ester, it is preferable to select a method of recrystallization from acetone.
  • the azilsartan shown by this can be manufactured.
  • the azilsartan alkyl ester to be used may be a novel crystal or may be recrystallized with a solvent containing a ketone solvent.
  • hydrolysis may be performed in the presence of a base or an acid to convert —COOR 1 (alkyl ester group) to —COOH (carboxylic acid).
  • R 1 has the same meaning as in formula (3). Is produced by performing the cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms.
  • R 1 is an alkyl group. Considering the stability of the ester protecting group-containing compound as a raw material, the stability of the azilsartan alkyl ester, and the ease of production of azilsartan, R 1 is preferably an alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, and an isobutyl group, and a methyl group is particularly preferable. In the following, description will be given in order.
  • the ester protecting group-containing compound represented by the formula (3) is not particularly limited, and can be produced by a known method. Specifically, it can be produced by the methods described in Non-Patent Document 1 and Patent Document 1. Specifically, it can be produced according to the following reaction formula.
  • the amidoxime compound represented by the formula (2) is a known compound, and its production method is described in Non-Patent Document 1 and Patent Document 1. Moreover, it is also preferable to use what was manufactured by 1st this invention. In the presence of a base, the amidoxime compound represented by the formula (2) can be reacted with the compound represented by XCOOR 2 to produce an ester protecting group-containing compound represented by the formula (3).
  • XCOOR 2 is reacted with a compound represented by the formula (2), X is a halogen atom, the same as R 2 in the ester protecting group-containing compound represented by R 2 is the formula (3) Yes, it is a protecting group for protecting the hydroxyl group.
  • X includes a chlorine atom, a bromine atom, and an iodine atom. Among them, a chlorine atom is preferable in consideration of industrial availability, reactivity, and the like.
  • R 2 includes a general protecting group for protecting a hydroxyl group.
  • Specific examples include an alkyl group which may have a substituent, a benzyl group, and a phenyl group which may have a substituent.
  • an unsubstituted alkyl group having 1 to 8 carbon atoms is preferable in view of industrial availability, role in the ester protecting group-containing compound, and finally removal.
  • This unsubstituted alkyl group may be a linear alkyl group or a branched alkyl group.
  • XCOOR 2 examples include methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, amyl chloroformate, 2-ethylhexyl chloroformate, hexyl chloroformate, chloroformate Examples include heptyl acid, chloromethyl chloroformate, 2-chloroethyl chloroformate, benzyl chloroformate, phenyl chloroformate, and 4-chlorophenyl chloroformate. Among these, it is preferable to use methyl chloroformate, ethyl chloroformate, propyl chloroformate and the like in view of industrial availability, reactivity, role in the ester protecting group-containing compound, and the like.
  • the amount of XCOOR 2 used is not particularly limited. Specifically, the amount of XCOOR 2 used may be 1 to 5 mol with respect to 1 mol of the compound represented by the formula (2).
  • the reaction is performed in the presence of a base.
  • a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide;
  • Organic bases such as methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N-dimethylaminopyridine, diazabicycloundecene, N-methylmorpholine Can be mentioned.
  • organic bases such as triethylamine, pyridine, and diisopropylethylamine are preferable in consideration of the progress of the reaction, ease of removal, treatment in the subsequent steps, and the like.
  • the above-mentioned base can be used as a single kind or a plurality of kinds of bases.
  • the reference base amount is the total amount of the plurality of types of bases.
  • the amount of the base used is not particularly limited. Specifically, the amount of the base used may be 1 to 5 mol with respect to 1 mol of the compound represented by the formula (2). As will be described later, when the ester group-containing compound is cyclized, it is preferably carried out in the presence of a base. Therefore, when the ester group-containing compound obtained by this reaction is cyclized, the cyclization reaction can be carried out with the base remaining.
  • the solvent to be used may be selected from among aprotic solvents which do not react with XCOOR 2. Specific examples include benzene, toluene, methylene chloride, chloroform, 1,4-dioxane and the like. One kind of these reaction solvents may be used, or two or more kinds of mixed solvents may be used.
  • the reaction it is preferable to stir and mix in the presence of a base so that the amidoxime compound represented by the formula (2) and XCOOR 2 are in sufficient contact with each other in a solvent.
  • the procedure for introducing these components into the reaction vessel is not particularly limited.
  • the conditions for carrying out the reaction are not particularly limited.
  • the reaction temperature is preferably ⁇ 10 to 10 ° C.
  • the reaction time is sufficient if it is 0.5 to 15 hours.
  • the ester protecting group-containing compound By reacting under the above conditions, the ester protecting group-containing compound can be produced.
  • the method for taking out the ester protecting group-containing compound from the reaction system is not particularly limited. Specifically, the ester protecting group-containing compound is dissolved in a water-insoluble solvent such as ethyl acetate, toluene, chloroform, methylene chloride, washed with water, concentrated, dried, etc. The compound can be removed. When a solvent that is hardly soluble in water is used as the solvent, the solution can be washed as it is.
  • a water-insoluble solvent such as ethyl acetate, toluene, chloroform, methylene chloride
  • the ester group-containing compound obtained under the above conditions is not particularly limited, but may have a purity of 90.0 to 99.5%. Moreover, the following cyclization reaction can also be implemented in the state which this extracted ester group containing compound contained the base by adjusting water washing.
  • the feature of the present invention is that the ester protecting group-containing compound is subjected to a cyclization reaction
  • R 1 has the same meaning as in formula (3). Is produced in a reaction solvent containing an alcohol having 1 to 8 carbon atoms. During this cyclization reaction, R 2 —OH is by-produced.
  • This cyclization reaction can proceed by heating. Specifically, by heating a reaction solution in which the ester protecting group-containing compound is dissolved in an alcohol having 1 to 8 carbon atoms, the cyclization reaction is promoted, and the ester protecting group-containing compound is converted to an azilsartan alkyl ester. be able to.
  • the ester protecting group-containing compound is dissolved in a reaction solvent and heated while being stirred and mixed.
  • the ester protecting group-containing compound and the reaction solvent may be heated while stirring to form a reaction solution, and the reaction solution may be heated as it is.
  • reaction solvent used in this cyclization reaction is a solvent containing an alcohol having 1 to 8 carbon atoms.
  • alcohols having 1 to 8 carbon atoms include methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, 2-methyl-2-propanol, 1 -Pentanol, 3-methyl-1-butanol, 1-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-methyl-2-pentanol, 2,4-dimethyl-3 -Pentanol, 3-ethyl-3-pentanol, octanol and the like.
  • a straight-chain or branched alcohol having 3 to 8 carbon atoms is used as a solvent capable of increasing the temperature during the cyclization reaction, increasing the reaction rate, and reducing impurities.
  • a straight-chain or branched alcohol having 3 to 8 carbon atoms is used as a solvent capable of increasing the temperature during the cyclization reaction, increasing the reaction rate, and reducing impurities.
  • 1-propanol, isopropanol, 1-butanol and 2-butanol are preferably used, and 1-propanol and 1-butanol are particularly preferable.
  • These alcohols having 1 to 8 carbon atoms can be used alone or a plurality of kinds of mixed solvents can be used.
  • the reference amount of the alcohol is the total amount of the mixed solvent.
  • the reaction solvent can also contain other solvents other than alcohols having 1 to 8 carbon atoms in a proportion of less than 50% by mass, but considering the ease of purification and the like, the other solvent is 10% by mass. The following is preferable, and 0% by mass is further preferable.
  • the amount of alcohol having 1 to 8 carbon atoms used in the reaction solvent is not particularly limited. Considering the efficiency of the reaction, reduction of impurities, and operability in the subsequent step, the amount of the alcohol having 1 to 8 carbon atoms in the reaction solvent is 3 to 30 ml with respect to 1 g of the ester protecting group-containing compound. preferable. By satisfying this range, after completion of the cyclization reaction, it becomes easy to cool and take out the azilsartan methyl ester as crystals. In order to further exert the above effects, the amount of the alcohol having 1 to 8 carbon atoms in the reaction solvent is more preferably 5 to 20 ml with respect to 1 g of the ester protecting group-containing compound. In addition, the said volume of a reaction solvent is a volume in 23 degreeC.
  • the reaction temperature of the cyclization reaction is preferably 50 ° C. or higher and the reflux temperature of the reaction solution or lower, and preferably 60 ° C. or higher and the reaction solution reflux temperature or lower in order to increase the reaction rate and reduce impurities. It is more preferable that the temperature be 70 ° C. or higher and the reflux temperature of the reaction solution or lower. Since the reflux temperature of the reaction solution varies depending on the reaction solvent used, the concentration of the ester protecting group-containing compound, and the type of R 2 —OH produced as a by-product, it cannot be generally limited. However, in order to further suppress the generation of impurities, the reaction temperature is preferably 100 ° C. or lower.
  • the cyclization reaction can be promoted according to the above conditions.
  • the reaction in order to shorten the reaction time, is preferably performed in the presence of a base. Specifically, it may be in a state where a base is contained in the reaction solution.
  • the base that can be used in the cyclization reaction is not particularly limited, and the above-mentioned inorganic bases and organic bases can be used. Among them, it is preferable to use an organic base such as triethylamine, pyridine, or diisopropylethylamine in order to improve the ease of purification and operability of the obtained azilsartan alkyl ester.
  • an organic base such as triethylamine, pyridine, or diisopropylethylamine in order to improve the ease of purification and operability of the obtained azilsartan alkyl ester.
  • the reference base amount is the total amount of the plurality of types of bases.
  • the base which remains when taking out this ester protective group containing compound can also be used.
  • the cyclization reaction can proceed without using a base.
  • the amount of the base used is preferably 0.01 to 5 mol with respect to 1 mol of the ester protecting group-containing compound.
  • the reaction rate can be increased, and the yield and purity of the azilsartan alkyl ester can be increased.
  • the amount of the base used is more preferably 0.1 to 1 mol with respect to 1 mol of the ester protecting group-containing compound.
  • the base and the ester protecting group-containing compound when a base is used, can be added in advance to the reaction solvent, and the mixture can be stirred and mixed while heating.
  • the base can be added to the reaction solution heated with stirring and mixing in order to promote the reaction from the middle.
  • the total amount of base used is the standard amount.
  • an azilsartan alkyl ester By performing the cyclization reaction under the above conditions, an azilsartan alkyl ester can be produced.
  • the method for taking out the obtained azilsartan alkyl ester from the reaction system is not particularly limited, and the methods described in Non-Patent Document 1 and Patent Document 1 can be employed.
  • the reaction solvent since the solvent containing 1 to 8 alcohols is used as the reaction solvent, it is preferable to employ the following method. Specifically, the reaction solution is cooled or a part of the reaction solvent is distilled off from the reaction solution to precipitate crystals of azilsartan alkyl ester in a reaction solvent containing an alcohol having 1 to 8 carbon atoms. It is preferable to take out the crystals. In particular, it is preferable to cool the reaction solution to precipitate crystals.
  • the amount of alcohol having 1 to 8 carbon atoms is preferably 3 to 30 ml with respect to 1 g of azilsartan alkyl ester.
  • the amount of alcohol having 1 to 8 carbon atoms is preferably 5 to 20 ml with respect to 1 g of azilsartan alkyl ester.
  • the amount of the alcohol having 1 to 8 carbon atoms is a volume at 23 ° C.
  • the cyclization reaction is preferably performed by heating.
  • the temperature of the reaction solution (reaction temperature) is 50 ° C. or higher. Therefore, the reaction solution after completion of the reaction is preferably cooled to a range of 30 ° C. or less, more preferably -10 to 30 ° C., particularly -10 to 10 ° C. preferable.
  • reaction temperature is 50 ° C. or higher. Therefore, the reaction solution after completion of the reaction is preferably cooled to a range of 30 ° C. or less, more preferably -10 to 30 ° C., particularly -10 to 10 ° C. preferable.
  • a seed crystal can also be used when the crystal is precipitated. And in this invention, if it cools and it adjusts so that the crystal
  • the reaction solution after completion of the reaction is cooled at a cooling rate of 10 to 30 ° C./hour, and is 30 ° C. or less, preferably 0 to 30 ° C., more preferably
  • the temperature is preferably -10 to 30 ° C, particularly preferably -10 to 20 ° C.
  • the temperature is 30 ° C. or less, preferably 0 to 30 ° C., more preferably ⁇ 10 to 30 ° C., particularly preferably ⁇ 10 to 20 ° C. It is preferable to leave it for more than an hour, preferably more than 2 hours and less than 20 hours.
  • the crystals of the precipitated azilsartan alkyl ester can be processed by a known method. Usually, it is preferable to take out the crystals by filtration, wash and dry. In order to obtain a higher purity azilsartan alkyl ester, it may be recrystallized with an alcohol having 1 to 8 carbon atoms.
  • the azilsartan alkyl ester obtained as described above becomes a solvate crystal containing an alcohol having 1 to 8 carbon atoms, even if recrystallized again with an alcohol having 1 to 8 carbon atoms. That is, it is considered that a part of the alcohol having 1 to 8 carbon atoms is taken into the crystal.
  • a crystal having a characteristic peak at 9 ⁇ 0.2 °, 10.9 ⁇ 0.2 ° can be obtained.
  • the crystal having the above peak is not in the prior art and is a new crystal form. This crystal may contain 0.5 to 5% by mass of 1-propanol (hereinafter, this crystal may be simply referred to as “new crystal”).
  • azilsartan can also be synthesized by hydrolyzing the azilsartan alkyl ester as it is.
  • the novel crystalline form of the azilsartan alkyl ester may be a solvate containing 0.5-5% by weight of 1-propanol.
  • ketone solvent to be used examples include acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone.
  • acetone is preferably used in order to improve purity and improve operability.
  • These ketone solvents can be used alone or a plurality of types of mixed solvents can be used. When a mixed solvent is used, the amount of the ketone solvent used as a reference is the total amount of the mixed solvent.
  • the solvent containing the ketone solvent may contain other solvents other than the ketone solvent at a ratio of less than 50% by mass, but considering the ease of purification, the other solvent is 10% by mass or less. It is preferable that it is 0% by mass.
  • the amount of ketone solvent to be used is not particularly limited. Specifically, the amount of the ketone solvent is preferably 3 to 30 ml, more preferably 5 to 20 ml, with respect to 1 g of the azilsartan alkyl ester crystal.
  • the crystal of the azilsartan alkyl ester is dissolved in a solvent containing a ketone solvent.
  • the crystals of the azilsartan alkyl ester are dissolved by heating to the reflux temperature of the solution (about 60 ° C.). Then, it is preferably cooled at a cooling rate of 10 to 30 ° C./hour and left standing for a certain time in a temperature range of 0 to 30 ° C., more preferably ⁇ 10 to 30 ° C., particularly preferably ⁇ 10 to 20 ° C.
  • the azilsartan shown by this can be manufactured.
  • the third aspect of the present invention provides following formula (4)
  • R 1 is an alkyl group
  • the description will be given in order.
  • R 1 is an alkyl group. Considering the stability of the ester protecting group-containing compound as a raw material, the stability of the azilsartan alkyl ester, and the ease of production of azilsartan, R 1 is preferably an alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group, and a methyl group is particularly preferable.
  • the target azilsartan alkyl ester used in the present invention is not particularly limited, and those synthesized by a known method can be used. For example, it is preferable to employ one manufactured by the manufacturing method described in the second aspect of the present invention.
  • the target azilsartan alkyl ester is obtained by performing a cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms as described in the second aspect of the present invention.
  • the target azilsartan alkyl ester obtained by the method can reduce impurities whose structure is unknown compared to the conventional azilsartan alkyl ester that is cyclized in a xylene solvent and precipitated in a solvent containing ethyl acetate. .
  • This conventional azilsartan alkyl ester tends to contain impurities having a molecular weight higher than that of the azilsartan alkyl ester (in the case of azilsartan methyl ester, it tends to contain impurities having a molecular weight of 10 more than that of the azilsartan methyl ester. ). Therefore, in the present invention, it is preferable to use the target azilsartan alkyl ester in which impurities are reduced by performing a cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms.
  • the target azilsartan alkyl ester is acetone, or acetone and alcohol. It is necessary to crystallize in a mixed solvent.
  • the solvent used in the present invention is acetone or a mixed solvent of acetone and alcohol.
  • the total volume of acetone and alcohol is 100
  • the volume ratio of acetone is 100 to 50
  • the volume ratio of alcohol is 0 to What becomes 50 is preferable.
  • the target azilsartan alkyl ester obtained by carrying out the cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms is used, it is not necessary to remove the alcohol strictly. Can be improved. Therefore, when the target azilsartan alkyl ester is a crude product containing alcohol, the amount of acetone used may be adjusted by measuring the amount of the alcohol.
  • the alcohol when alcohol is used, is preferably an alcohol having 1 to 8 carbon atoms.
  • a linear or branched alcohol having 3 to 8 carbon atoms in consideration of the yield and the effect of reducing impurities of desethyl and dimers of the azilsartan alkyl ester, it is preferable to use a linear or branched alcohol having 3 to 8 carbon atoms.
  • 1-propanol, isopropanol, 1-butanol and 2-butanol are preferably used, and 1-propanol and 1-butanol are particularly preferable.
  • One kind of these alcohols can be used, or a plurality of kinds can be mixed and used.
  • the volume ratio of acetone is 99 to 51 and the volume ratio of alcohol is 1 to 49.
  • the volume ratio of acetone is 90 to 60, and the volume ratio of alcohol. Is preferably 10 to 40.
  • the amount of acetone or the mixed solvent of acetone and alcohol to be used is not particularly limited, but is preferably 3 to 30 ml with respect to 1 g of the target azilsartan alkyl ester crystal, It is preferably 5 to 20 ml.
  • the said volume of the solvent to be used is a volume in 23 degreeC.
  • the reference amount of solvent is the total amount of acetone and alcohol.
  • the target azilsartan alkyl ester is dissolved in acetone or a mixed solvent of acetone and alcohol, preferably heated to the reflux temperature (about 60 ° C.) of the resulting solution, and then 10 It is preferable to cool at a cooling rate of ⁇ 30 ° C./hour, and hold for a certain time in a temperature range of preferably 0 to 30 ° C., more preferably ⁇ 10 to 30 ° C., particularly preferably ⁇ 10 to 20 ° C.
  • azilsartan alkyl ester novel azilsartan methyl ester
  • the azilsartan methyl ester in which R 1 is a methyl group, which is a suitable compound is obtained by X-ray diffraction using Cu—K ⁇ rays.
  • azilsartan methyl ester obtained by crystallization in acetone or a mixed solvent of acetone and alcohol has a novel crystal form in which at least two melting points exist (hereinafter referred to as “quasicrystal”). ”).
  • the azilsartan methyl ester obtained by crystallization in acetone or a mixed solvent of acetone and alcohol has a melting point measured under the conditions of the differential scanning calorimeter shown in the examples at least 150 to 165 ° C., 185 Observed at ⁇ 195 ° C.
  • the melting point determined by differential scanning calorimetry (DSC) measurement is the peak top temperature of the endothermic peak.
  • This new quasicrystal is considered not to be a complete crystal because it has a lower melting point than the conventionally known azilsartan alkyl ester. Therefore, although the purity is high, since it can be easily dissolved, it can be suitably used for the next hydrolysis reaction.
  • the heat of fusion of the quasicrystalline azilsartan methyl ester cannot be obtained by drawing a beautiful tangent to the endothermic peak as shown in the chart of FIG. This is presumably due to the fact that the azilsartan methyl ester is an unstable crystal. Therefore, the heat of fusion is not an accurate value, but when the heat of fusion is obtained as shown in FIG. 5, the melting point in the temperature range of 150 to 165 ° C. (hereinafter, sometimes simply referred to as “low melting point”).
  • the heat of fusion with respect to the melting point in the range of 185 to 195 ° C. (hereinafter sometimes simply referred to as “high melting point”) is 40 to 70 J / g. preferable.
  • the heat of fusion related to the low melting point is preferably 4 to 10 J / g
  • the heat of fusion related to the high melting point is preferably 50 to 60 J / g.
  • the azilsartan shown by this can be manufactured.
  • the obtained azilsartan is not particularly limited, and may be purified by a known method to obtain a drug substance.
  • a known method to obtain a drug substance.
  • the method using methods, such as recrystallization, reslurry, and column chromatography, is mentioned.
  • the azilsartan produced according to the first to third inventions has the following formula (6) as an impurity:
  • the azilsartan dimer shown by may be included.
  • a step of separating the crystals of azilsartan from the solution may be added.
  • Crude azilsartan means azilsartan containing azilsartan dimers as impurities.
  • the crude azilsartan may be 96.0-99.0% pure azilsartan as determined by high performance liquid chromatography (HPLC) analysis.
  • the crude azilsartan to be purified may contain 0.01 to 0.50% of the azilsartan dimer.
  • the azilsartan dimer to be reduced is considered to be by-produced as follows. That is, the amidoxime compound (compound of formula (2)) used as a raw material first reacts with azilsartan (compound of formula (5)) that is considered to have been produced when the amidoxime compound is cyclized. do it, Following formula (12)
  • R 1 is an alkyl group
  • the activated carbon to be used is not particularly limited, but the specific surface area determined by the BET method is 1000 to 3500 m 2 / g and the cumulative pore volume is 0.6 to 1.5 mL / g. Is preferred. By using activated carbon having the physical properties in this range, the azilsartan dimer can be more effectively reduced.
  • the activation (activation) method of the activated carbon to be used is not particularly limited, and both zinc chloride coal obtained by a chemical activation method and steam coal obtained by a steam activation method can be suitably used.
  • the type of activated carbon is not particularly limited, and any activated carbon can be used as long as it satisfies the above properties, such as powdered coal, crushed coal, granular coal, granulated coal, and formed coal. Among these, considering the ease of handling, the removal efficiency of the activated carbon itself, etc., it is preferable to use powdered coal or granular coal.
  • activated carbon examples include refined white birch, characteristic white birch, granular white birch, white birch A, white birch P, white birch C, white birch M (above, manufactured by Osaka Gas Chemicals), Dazai A, Dazai CA, Dazai K, Dazai M. (Above, manufactured by Phutamura Chemical).
  • the solution of the crude azilsartan to be brought into contact with the activated carbon is not particularly limited as long as the crude azilsartan containing the azilsartan dimer as an impurity is dissolved. Therefore, the solvent used in the crude azilsartan solution may be an organic solvent or water as long as the crude azilsartan can be dissolved. Among them, as described above, it is preferable to contact activated carbon with a solution containing crude azilsartan obtained by hydrolyzing an azilsartan alkyl ester (a solution containing crude azilsartan obtained after the hydrolysis reaction). In this case, the solution containing crude azilsartan can contain a base.
  • the solution obtained by dissolving the azilsartan taken out from the solution in a basic aqueous solution and the activated carbon can be contacted again.
  • the method of bringing the crude azilsartan solution into contact with the activated carbon is not particularly limited.
  • a method of simultaneously mixing crude azilsartan, activated carbon, and a solvent capable of dissolving crude azilsartan a method of preparing a solution in which crude azilsartan is dissolved, a method of adding activated carbon to the solution and mixing, or a method of filling activated carbon
  • a method of allowing the solution to pass through a column can be employed.
  • the amount of activated carbon used may be appropriately determined depending on the type of activated carbon, the amount of impurities, and the like.
  • the mixing of the solution and activated carbon is preferably carried out with stirring.
  • the temperature at the time of stirring and mixing is preferably 15 to 35 ° C., particularly preferably 20 to 30 ° C.
  • the contact time with the activated carbon is not particularly limited, and it is usually sufficient to carry out at the temperature in the range of 1 to 5 hours.
  • Method for removing activated carbon As described above, after bringing the crude azilsartan solution into contact with the activated carbon, the activated carbon is then separated from the mixture and the separated solution is recovered.
  • the method for separating the activated carbon is not particularly limited, and can be carried out by a known method. For example, a separation method such as decantation, filtration, and centrifugal filtration may be employed. At this time, a filter aid such as celite or radiolite may be used for the purpose of improving the efficiency of filtration.
  • the method for fractionating the crystals of azilsartan from the separated liquid is not particularly limited and can be carried out by a known method.
  • a method of fractionating azilsartan crystals by directly distilling off the solvent from the separated solution, or a method of precipitating azilsartan crystals by neutralizing the separated solution can be employed without particular limitation.
  • the crystals of azilsartan precipitated by the above method can be separated (sorted) by a known method. Specifically, separation methods such as decantation, reduced pressure / pressure filtration, and centrifugal filtration may be employed. Moreover, it is preferable to wash
  • the crystals of azilsartan thus obtained are wet bodies, and a dried form of azilsartan crystals is obtained by drying at 30 to 50 ° C. for 3 to 20 hours.
  • the azilsartan dimer content is reduced particularly by separating the crystals of azilsartan from the solution.
  • High-purity azilsartan crystals can be obtained.
  • the activated carbon having a specific surface area determined by the BET method of 1000 to 3500 m 2 / g and a cumulative pore volume of 0.6 to 1.5 mL / g, The content of the monomer can be further reduced, and crystals of azilsartan with higher purity can be obtained.
  • Each of the crystals of azilsartan produced according to the first to third inventions is very hardly soluble in an organic solvent. For this reason, when a purification operation is performed using an organic solvent, a large amount of the organic solvent is required.
  • the crystalline form of the azilsartan produced according to the first to third inventions described above has very high solubility in various solvents including alcohols such as methanol and ethanol and esters such as ethyl acetate. It is also preferable that
  • the azilsartan of this invention which has this crystal structure may be called "Azilsartan M-type crystal".
  • ⁇ 0.2 ° which is a measurement error of the X-ray diffraction angle includes a range of ⁇ 0.2 ° by rounding off.
  • the X-ray diffraction measurement result of this azilsartan M-type crystal is shown in FIG.
  • a peak having an intensity of less than 7% with respect to the maximum peak intensity is regarded as noise or the like, and does not correspond to a characteristic peak in the present invention.
  • the azilsartan M-type crystals are alcohols such as methanol and ethanol; esters such as ethyl acetate; Ketones: The solubility of ethers such as tetrahydrofuran in organic solvents is improved. Specifically, at room temperature, azilsartan M-type crystals can be dissolved about 7 to 10 times in the same amount of methanol than known azilsartan crystals.
  • the azilsartan M-type crystal has a lower melting point than the known azilsartan crystal.
  • the melting point determined by differential scanning calorimetry (DSC) measurement is 115 ° C. or higher and 135 ° C. or lower.
  • the melting point determined by differential scanning calorimetry (DSC) measurement refers to the peak top temperature of the endothermic peak obtained by the measurement.
  • Azilsartan M-type crystals can be produced by adding a solvent of ketones and / or esters to a solution obtained by dissolving azilsartan in dimethylformamide to precipitate azilsartan M-type crystals.
  • azilsartan is a hydrate or solvate
  • the number of molecules of water or solvent is not particularly limited.
  • a solvent of dimethylformamide and ketones and / or esters is used in the production of azilsartan M-type crystals, it may be a wet body containing the organic solvent, and other solvents may be used during crystallization. It may remain within a range that does not affect the above. Specifically, it may remain in an amount of 50% by mass or less of the azilsartan. Most preferably, no solvent other than the organic solvent is contained.
  • the purity of the azilsartan used is not particularly limited, and those obtained by the first to third inventions can be used as they are.
  • azilsartan solution is first obtained by dissolving azilsartan in dimethylformamide.
  • the dimethylformamide used is not particularly limited, and a commercially available product can be used as it is.
  • the amount of dimethylformamide used may be appropriately determined depending on the crystal form of azilsartan to be used, but is generally 0.5 mL to 10 mL with respect to 1 g of azilsartan. When the amount of dimethylformamide used increases, the yield decreases, so that it is preferably 0.5 mL or more and 5 mL or less.
  • the volume of a solvent shall be in 25 degreeC.
  • the temperature at which azilsartan is dissolved may be appropriately determined depending on the crystal form of azilsartan used and the amount of dimethylformamide, and it is preferably dissolved in the range of 10 ° C to 50 ° C. As a matter of course, when there is a substance that does not completely dissolve, the substance that does not dissolve can be filtered and processed. Further, the method for obtaining the azilsartan solution is not particularly limited, and the solution may be prepared by mixing azilsartan and dimethylformamide, and the mixing method and order are not particularly limited.
  • the method for producing azilsartan M-type crystals is characterized in that a solvent for ketones and / or esters is added to the obtained azilsartan solution to precipitate azilsartan M-type crystals.
  • a solvent for ketones and / or esters is added to the obtained azilsartan solution to precipitate azilsartan M-type crystals.
  • Solvents added to the azilsartan solution are from ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone and cyclohexanone; and / or esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. You can choose.
  • a solvent of an ester it is preferable to add a solvent of an ester, and it is most preferable to use ethyl acetate among them.
  • these ketone solvents and esters can be mixed and added.
  • by adding a solvent of ketones and / or esters to precipitate azilsartan it is possible to precipitate azilsartan M-type crystals having improved solubility in organic solvents.
  • the amount of ketones and / or esters used in the azilsartan solution may be appropriately determined depending on the type of solvent selected. Usually, it may be 1 mL or more and 50 mL or less with respect to 1 mL of dimethylformamide used in the preparation of the azilsartan solution, and it is preferably 5 mL or more and 20 mL or less in consideration of yield and operability.
  • the temperature at which the ketone and / or ester solvent is added is not particularly limited, and after confirming that azilsartan is dissolved in dimethylformamide, it can be added immediately at the temperature, but 30 ° C. or less. It is more preferable to add at. By adding at 30 ° C.
  • the method of adding the ketone and / or ester solvent is not particularly limited, and either a method of adding the whole amount at once or a method of adding it in several divided portions can be employed.
  • the azilsartan M-type crystals are precipitated by stirring at a constant temperature.
  • the temperature maintained at this time may be ⁇ 5 ° C. or higher and 30 ° C. or lower.
  • it is preferably maintained at 0 ° C. or higher and 10 ° C. or lower.
  • the holding time may be appropriately determined depending on the holding temperature, but it is usually preferably 5 hours or longer. At this time, if crystals of azilsartan are difficult to precipitate, seed crystals can be added.
  • the azilsartan M-type crystals thus precipitated can be isolated by solid-liquid separation by filtration, centrifugation, or the like, and then drying by a method such as natural drying, blast drying, or vacuum drying.
  • the azilsartan obtained by this method is an azilsartan M-type crystal having a novel crystal structure.
  • the azilsartan M-type crystal of the present invention has improved solubility in organic solvents, and the solubility of alcohols, esters, ketones, and ethers in solvents is extremely high compared to known crystal forms. Accordingly, when performing purification operations on azilsartan M-type crystals, purification operations such as recrystallization can be easily performed using solvents of alcohols, esters, ketones, and ethers.
  • the amidoxime desethyl derivative is about 1.8 minutes, the amidoxime compound is about 2.8 minutes, the amidoxime ethyl form is about 4.0 minutes, the amide form is about 8.5 minutes, the nitrile The desethyl compound is about 11.2 minutes, the nitrile compound is about 25.0 minutes, the ester protecting group-containing compound A (R 1 : methyl group, R 2 : ethyl group) is about 16.2 minutes, the ester protection Group-containing compound B (R 1 : methyl group, R 2 : 2-ethylhexyl group) is about 52.3 minutes, said azilsartan methyl ester is about 14.5 minutes, said desethyl body is about 7.0 minutes, said azil A peak is observed at about 7.3 minutes for sultan, about 49.1 minutes for the dimer, and about 5.5 minutes for impurities whose molecular weight is 10 larger than that of azilsartan methyl ester.
  • the purity values of the amidoxime compound, the ester protecting group-containing compound, the azilsartan methyl ester, and the azilsartan are all the area values of all peaks measured under the above conditions (from the solvent) Is the ratio of the peak area value of each compound to the total.
  • Example and Comparative Example According to First Invention [Example 1] The nitrile compound (5 g, 12.2 mmol) was weighed in a 100 mL three-necked flask equipped with two stirring blades with a diameter of 2.5 cm, and 1-propanol (50 mL), a commercially available 50% by mass hydroxylamine aqueous solution (4.0 g, 60.60 mL). 8 mmol) was added, and the mixture was heated to the reflux temperature (about 92 ° C.), and then reacted at the same temperature for 12 hours.
  • 1-propanol 50 mL
  • a commercially available 50% by mass hydroxylamine aqueous solution 4.0 g, 60.60 mL
  • amidoxime compound purity 82.2%, the amide compound: 9.1%, the nitrile compound: 2.2%, the amidoxime desethyl compound: 6.0%, the amidoxime ethyl compound: 0.3%, Nitrile desethyl compound: 0.05%.
  • Example 2 70 g (170.1 mmol) of the nitrile compound was weighed into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, 700 mL of 1-propanol, 5.16 g (51.0 mmol) of triethylamine, and a commercially available 50% by mass hydroxyl group. After adding 56.2 g (850.5 mmol) of an aqueous amine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours.
  • the amidoxime compound Purity of the amidoxime compound: 83.9%, the amide body: 2.4%, the nitrile compound: 2.4%, the amidoxime desethyl body: 7.6%, the amidoxime ethyl body: 0.2% The nitrile desethyl compound was 0.01%.
  • Example 3 Nitrile compound 5 g (12.2 mmol) was weighed into a 100 mL three-necked flask equipped with two 2.5 cm diameter stirring blades, 1-propanol 50 mL, triethylamine 0.62 g (6.1 mmol), 50% by mass commercially available. After adding 4.0 g (60.8 mmol) of an aqueous hydroxylamine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours.
  • amidoxime compound Purity of the amidoxime compound: 84.2%, the amide body: 1.8%, the nitrile compound: 2.6%, the amidoxime desethyl body: 7.4%, the amidoxime ethyl body: 0.2% The nitrile desethyl compound was 0.01%.
  • Example 4 In Example 3, the same operation was performed except that the reaction solvent was changed from 1-propanol to 1-butanol and the amount of triethylamine used was changed from 0.62 g (6.1 mmol) to 0.37 g (3.66 mmol). .
  • Example 5 In Example 3, the same operation was performed except that the base used was changed from triethylamine to pyridine and the amount of the base used was changed from 0.62 g (6.1 mmol) to 0.37 g (3.66 mmol).
  • Example 6 In Example 3, the same operation was performed except that the amount of triethylamine used was changed from 0.62 g (6.1 mmol) to 0.12 g (1.22 mmol).
  • Example 7 In Example 1, the same operation was performed except that the amount of 1-propanol used was changed from 50 mL to 75 mL.
  • Example 8 (Synthesis of azilsartan methyl ester) 40 g of the amidoxime compound obtained in Example 2 was weighed into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, dimethyl sulfoxide 350 mL, 1,1′-carbonylimidazole 17.5 g, diazabicyclo 15.5 g of undecene was added, and the reaction was carried out with stirring at room temperature for 4 hours. 1500 mL of water was weighed into a separately prepared 3 L three-necked flask, and the reaction solution was slowly added dropwise.
  • the precipitated crystals of azilsartan methyl ester are collected by filtration under reduced pressure, dried at 50 ° C., and then recrystallized from 400 mL of acetone. The obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C. to obtain 32.0 g of crystals of azilsartan methyl ester (purity of azilsartan methyl ester: 99. 4%).
  • Example 9 Synthesis of azilsartan After weighing 20 g of azilsartan methyl ester obtained in Example 8 into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, adding 200 mL of a 1.25 M aqueous sodium hydroxide solution and heating to 50 ° C., The reaction was carried out at the same temperature for 3 hours. After cooling the reaction solution to 45 ° C., 100 mL of acetone, 75 mL of acetic acid, and 70 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C.
  • the amidoxime compound purity 42.6%, the amide compound: 37.0%, the nitrile compound: 4.5%, the amidoxime desethyl compound: 9.3%, the amidoxime ethyl compound: 4.8%, The nitrile desethyl form: 1.0%.
  • amidoxime compound 72.0%, the amide form: 9.8%, the nitrile compound: 0.5%, the amidoxime desethyl form: 9.3%, the amidoxime ethyl form: 1.0% The nitrile desethyl compound was 0.2%.
  • Example 10 5 g (9.7 mmol) of the ester protecting group-containing compound A obtained in Production Example 1 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, 45 mL of 1-propanol was added, and the reflux temperature was increased. After heating to (about 95 ° C.), the reaction was carried out at the same temperature for 16 hours. The purity of the azilsartan methyl ester was 91.5%, and the ester protecting group-containing compound A was 1.8%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour, and stirred at 0 ° C. for 14 hours.
  • Example 11 10 g (19.4 mmol) of the ester protecting group-containing compound A obtained in Production Example 1 was weighed in a 200 mL three-necked flask equipped with two stirring blades having a diameter of 5 cm, and 90 mL of 1-propanol and 0.4 g of triethylamine (3 g .9 mmol) was added and heated to the reflux temperature (about 94 ° C.), followed by reaction at the same temperature for 9 hours. The purity of the azilsartan methyl ester was 93.0%, and the ester protecting group-containing compound A was 0.7%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C.
  • Example 12 5 g (8.3 mmol) of the ester protecting group-containing compound B obtained in Production Example 2 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, and 45 mL of 1-propanol and 0.2 g of triethylamine were measured. (1.7 mmol) was added, and the mixture was heated to the reflux temperature (about 94 ° C.), and then reacted at the same temperature for 10 hours. The purity of the azilsartan methyl ester was 91.7%, and the ester protecting group-containing compound B was 0.6%. The reaction solution after the reaction was cooled to 0 ° C.
  • Example 13 In Example 11, the same operation was performed except that the amount of triethylamine used was changed from 0.4 g (3.9 mmol) to 1.96 g (19.4 mmol). The reaction was complete in 6 hours.
  • Example 14 In Example 10, the same operation was performed except that the reaction solvent was changed from 1-propanol to 1-butanol.
  • Example 15 In Example 10, the same operation was performed except that the amount of 1-propanol used was changed from 45 mL to 125 mL.
  • Example 16 In Example 11, the same operation was performed except that the base used was changed from triethylamine to pyridine.
  • Example 17 (Synthesis of azilsartan) After weighing 5 g of azilsartan methyl ester obtained in Example 11 into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, adding 50 mL of a 1.25 M aqueous sodium hydroxide solution and heating to 50 ° C., The reaction was carried out at the same temperature for 3 hours. After the reaction solution was cooled to 45 ° C., 25 mL of acetone, 17 mL of acetic acid, and 17 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C.
  • Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 10.8%.
  • Example 18 (crystallization of azilsartan methyl ester) Weigh 10 g of the target azilsartan methyl ester obtained in Production Example 3 in a 200 mL three-necked flask equipped with two stirring blades with a diameter of 5 cm, add 100 mL of acetone, and heat to reflux temperature (about 57 ° C.). Azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried under reduced pressure at 40 ° C.
  • Example 19 (Recrystallization of azilsartan methyl ester) Weigh 5 g of the target azilsartan methyl ester obtained in Production Example 3 in a 100 mL three-necked flask equipped with two stirring blades with a diameter of 3.5 cm, add 30 mL of acetone and 20 mL of 1-propanol, and heat to reflux temperature. The target azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours.
  • Example 20 (crystallization of azilsartan methyl ester) The same operation as in Example 19 was performed except that 1-propanol was changed to 1-butanol.
  • Example 21 (crystallization of azilsartan methyl ester)
  • a 100 mL three-necked flask equipped with two stirring blades with a diameter of 3.5 cm weigh 4 g of the target azilsartan methyl ester produced by the method of Comparative Example 5 below, add 40 mL of acetone, and heat to reflux temperature.
  • the subject azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 14 hours.
  • Example 22 (Recrystallization of azilsartan methyl ester) The azilsartan methyl ester produced in Example 21 was used as the target azilsartan methyl ester.
  • Example 21 The same operation as in Example 21 was repeated using 2 g of azilsartan methyl ester produced in Example 21.
  • Example 23 (Synthesis of azilsartan) 5 g of azilsartan methyl ester obtained in Example 19 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, 50 mL of a 1.25 M aqueous sodium hydroxide solution was added, and the mixture was heated to 50 ° C. Then, reaction was performed at the same temperature for 3 hours. After the reaction solution was cooled to 45 ° C., 25 mL of acetone, 17 mL of acetic acid, and 17 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C.
  • the reaction was carried out with stirring at 0 ° C. for 2 hours.
  • the solution after the reaction was heated to 20 ° C., and 480 mL of water was added to extract the organic layer.
  • the obtained organic layer was concentrated under reduced pressure to obtain the ester protecting group-containing compound (a compound in which R 1 is a methyl group and R 2 is an ethyl group) as a residue.
  • the purity of the ester group-containing compound was 96.1%, and the amidoxime compound was 0.14%.
  • the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 107.6 g of the azilsartan methyl ester crystals (purity of azilsartan methyl ester: 97.3). %, The azilsartan methyl ester desethyl compound: 0.14%, and the azilsartan methyl ester dimer compound: 0.20%) (yield: 84.7%). Moreover, an impurity having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed.
  • the reaction was carried out with stirring at 0 ° C. for 1 hour.
  • the solution after the reaction was heated to 20 ° C., and 270 mL of ethyl acetate and 60 mL of water were added to extract the organic layer.
  • the obtained organic layer was further washed with 60 mL of water, and then the organic layer was concentrated under reduced pressure.
  • the ester protecting group-containing compound (a compound in which R 1 is a methyl group and R 2 is a 2-ethylhexyl group) Obtained.
  • the purity of the ester group-containing compound was 94.5%, and the amidoxime compound was 1.26%.
  • Example 24 (Production of azilsartan; with activated carbon treatment) (Hydrolysis) 5 g of azilsartan methyl ester obtained in Production Example 5 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, added with 40 mL of a 1.25 M aqueous sodium hydroxide solution, and heated to 70 ° C. Thereafter, the reaction was carried out at the same temperature for 2 hours.
  • the crude azilsartan solution after the reaction had azilsartan purity: 99.61%, azilsartan desethyl compound: 0.06%, and azilsartan dimer: 0.08%.
  • Table 7 shows the results of the azilsartan purity and impurity amount of the crude azilsartan solution after the reaction.
  • Example 25 to 26 (Hydrolysis) A hydrolysis reaction was carried out in the same manner as in Example 24 except that the azilsartan alkyl ester of the production example shown in Table 7 was used as a raw material. Table 7 shows the purity of the crude azilsartan solution after the hydrolysis reaction and the measurement results of the amount of impurities.
  • Example 27 to 28 (Hydrolysis) A hydrolysis reaction was performed in the same manner as in Example 24.
  • Table 7 shows the measurement results of the purity and impurity amount of the crude azilsartan solution after the reaction.
  • azilsartan crystals were taken out from the reaction solution obtained in the same manner as in Reference Example 1. The purity and the amount of impurities were similarly measured for the obtained crystals of azilsartan. The results are shown in Table 8.
  • Example 33 (First step: Hydroxyamidination) 70 g (170.1 mmol) of the nitrile compound was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, 700 mL of 1-propanol, 5.16 g (51.0 mmol) of triethylamine, and a commercially available 50% by mass hydroxyl group. After adding 56.2 g (850.5 mmol) of an aqueous amine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours.
  • the nitrile desethyl compound was 0.01%.
  • the solution after the reaction was cooled to 20 ° C. at a rate of 20 ° C./hour and stirred at 20 ° C. for 13 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C.
  • the filtrate was filtered under reduced pressure to remove purified white glaze, and the obtained filtrate was heated to 40 ° C., and then 260 mL of methanol and 29.2 mL of acetic acid were added at the same temperature to precipitate crystals of azilsartan.
  • the reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours.
  • the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C.

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Abstract

La présente invention concerne : un procédé de production d'un composé d'amidoxime, où un composé nitrile et de l'hydroxylamine et/ou un sel acide d'hydroxylamine sont mis en réaction l'un avec l'autre dans un solvant de réaction qui contient un alcool ayant de 2 à 7 atomes de carbone ; un procédé de production d'un ester d'alkyle d'azilsartan, dans lequel un composé contenant un groupe protecteur d'ester est soumis à une réaction de cyclisation dans un solvant de réaction qui contient un alcool ayant de 1 à 8 atomes de carbone ; un procédé de production d'un ester d'alkyle d'azilsartan, dans lequel un ester d'alkyle d'azilsartan est cristallisé dans de l'acétone ou dans un solvant mixte d'acétone et d'alcool; et un procédé de production d'azilsartan, dans lequel un ester d'alkyle d'azilsartan est hydrolysé.
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JP2021001140A (ja) * 2019-06-21 2021-01-07 金剛化学株式会社 安定なアジルサルタン微細結晶の製造方法
JP7486763B2 (ja) 2019-06-21 2024-05-20 金剛化学株式会社 安定なアジルサルタン微細結晶の製造方法
JP2024091928A (ja) * 2019-06-21 2024-07-05 金剛化学株式会社 安定なアジルサルタン微細結晶の製造方法
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