WO2015163446A1 - Method for producing imidazole compound - Google Patents

Method for producing imidazole compound Download PDF

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WO2015163446A1
WO2015163446A1 PCT/JP2015/062504 JP2015062504W WO2015163446A1 WO 2015163446 A1 WO2015163446 A1 WO 2015163446A1 JP 2015062504 W JP2015062504 W JP 2015062504W WO 2015163446 A1 WO2015163446 A1 WO 2015163446A1
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formula
compound represented
production method
salt
compound
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Japanese (ja)
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雄志 北村
克昭 藤原
義和 森
孝之 愛宕
小川　暁
務 松村
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協和発酵キリン株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

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  • the present invention relates to a method for producing an imidazole compound.
  • R 1 represents an optionally substituted lower alkyl or the like
  • R 2 represents an optionally substituted aliphatic heterocyclic group or the like
  • R 3 represents a substituted Represents an aromatic heterocyclic group which may have a group
  • n represents an integer of 0 to 3
  • CBD2 cannabinoid type 2
  • Patent Document 1 it is shown that, for example, a compound represented by the formula (IA) can be produced according to the following scheme (see Example 186).
  • Tf represents trifluoromethylsulfonyl
  • Bu represents n-butyl
  • Ac represents acetyl
  • dppp represents 1,3-bis (diphenylphosphino) propane
  • n Pr represents n -propyl.
  • Me represents methyl
  • WSC represents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • HOBt represents 1-hydroxybenzotriazole
  • An object of the present invention is an imidazole compound represented by formula (I) having a CB2 receptor modulating action and useful as a therapeutic and / or prophylactic agent for pain and the like, and formula (VI) which is an intermediate for the production thereof. It is providing the manufacturing method etc. of the tetrahydrofuran compound represented. Another object is to provide a crystalline form of the imidazole compound represented by the formula (I) useful for use as a pharmaceutical product.
  • R 1 , R 2a and R 2b are the same or different and represent lower alkyl, and n represents an integer of 1 to 7)
  • the present invention relates to the following (1) to (27).
  • a compound represented by formula (II) or a salt thereof is reacted with an alkyl metal reagent, a boron reagent, and a compound represented by formula (III) or a salt thereof,
  • R 1 , R 2a and R 2b are the same or different and represent lower alkyl
  • a method for producing an imidazole compound or a salt thereof (2) A compound represented by the formula (II) or a salt thereof is reacted with an alkyl metal reagent and a boron reagent, and then the resulting reaction product is converted to a compound represented by the formula (III) or a salt thereof and a palladium catalyst. And reaction in the presence of a base, formula (I)
  • the compound represented by the formula (II) or a salt thereof is Step (i): a step of obtaining a compound represented by the formula (VI) by reacting a compound represented by the formula (IV) and a compound represented by the formula (V) in the presence of a base.
  • step (i) is an organic base selected from triethylamine, N-methylimidazole, diazabicycloundecane, diisopropylethylamine, pyridine, N-methylpiperidine and morpholine.
  • step (i) is triethylamine.
  • the base used in step (ii) is a metal salt of an alkylamine selected from hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium and lithium diisopropylamide (12) to (14)
  • n is 3.
  • 2 shows a powder X-ray crystal diffraction pattern of type I crystal of compound (IA).
  • the vertical axis represents diffraction intensity (counts per second), and the horizontal axis represents 2 ⁇ (°).
  • 2 shows a powder X-ray crystal diffraction pattern of a type II crystal of compound (IA).
  • the vertical axis represents diffraction intensity (counts per second), and the horizontal axis represents 2 ⁇ (°).
  • Examples of the lower alkyl include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Examples include isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • n, R 1 , R 2a and R 2b are as defined above.
  • Compound (VI) is obtained by reacting Compound (IV) in an organic solvent in the presence of a base at a temperature between ⁇ 50 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 20 ° C. It can manufacture by making it react.
  • Compound (IV) can be obtained, for example, by the method described in WO2008 / 029825 or the like, or a method analogous thereto.
  • the base include organic bases such as triethylamine, N-methylimidazole, diazabicycloundecene (DBU), diisopropylethylamine, pyridine, N-methylpiperidine, morpholine, and metal bases such as potassium carbonate and calcium carbonate. .
  • the base is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (IV).
  • Compound (V) can be obtained as a commercially available product, for example, by the method described in the literature (J. of Chem. Soc. London, 1957, p.2640-2645) or the like, or a method analogous thereto.
  • Compound (V) is used in an amount of, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (IV).
  • organic solvent examples include ether solvents such as tetrahydrofuran (THF) and t-butyl methyl ether, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylimidazolidinone (DMI), Examples include amide solvents such as N-methylpyrrolidine (NMP), ketone solvents such as ethyl methyl ketone, nitrile solvents such as acetonitrile, and dimethyl sulfoxide (DMSO). These may be used alone or in combination. it can.
  • the organic solvent is generally used in a volume of 1 to 20 volume / weight (v / w), preferably 2 to 8 v / w, relative to compound (IV).
  • the base to be used is preferably triethylamine or the like
  • the organic solvent to be used is preferably THF or the like.
  • the compound (VI) can be precipitated as a solid with good purity and ease by adding a poor solvent such as water to the reaction mixture.
  • the addition of a poor solvent can be performed by first dropping a mixed solvent of DMA and water (mixing volume ratio 1: 1), followed by dropwise addition of water, so that a solid can be gently precipitated, and a high purity compound. (IV) can be obtained.
  • compound (VI) is stable and easy to handle, and is convenient in terms of operation when industrial mass synthesis is intended, and this production method is an excellent production method.
  • Compound (II) is obtained by converting Compound (VI) from Compound (VII) in an organic solvent in the presence of a base at a temperature between ⁇ 50 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 40 ° C. It can manufacture by making it react.
  • the base examples include metal salts of alkylamines such as hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium, lithium diisopropylamide (LDA), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. And metal bases such as lithium hydroxide.
  • the base is used, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (VII).
  • Compound (VII) can be obtained, for example, by the method described in WO2008 / 029825 or the like, or a method analogous thereto.
  • Compound (VI) is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (VII).
  • the organic solvent include ether solvents such as THF and t-butyl methyl ether, amide solvents such as DMF, DMA, DMI, and NMP, nitrile solvents such as acetonitrile, DMSO, and the like. It can be used by mixing.
  • the organic solvent is generally used in a volume of 1 to 20 v / w, preferably 2 to 8 v / w, relative to compound (VI).
  • the base to be used is preferably hexamethyldisilazane lithium or the like, and the reaction solution becomes uniform by selecting the base.
  • the reproducibility of this process can be improved.
  • the organic solvent to be used a mixed solvent of THF and DMA (mixing volume ratio 3: 5) is preferable, and the solvent is excellent in solubility of the compound (VII).
  • the reaction mixture is neutralized with an acid such as hydrochloric acid, and a poor solvent such as water is added to the solvent, whereby the compound (II) is easily purified with high purity and yield. It can be deposited as a solid.
  • 1-propanol to the reaction mixture before neutralizing the reaction mixture with acid, a solid can be slowly precipitated, and a high purity compound (II) can be obtained. It becomes.
  • Compound (I) is obtained by reacting (a) Compound (II) with an alkyl metal reagent in an organic solvent at a temperature between ⁇ 100 ° C. and 10 ° C., preferably at a temperature between ⁇ 20 ° C. and 5 ° C. (B) then boron reagent is added to the reaction mixture and at a temperature between ⁇ 100 ° C. and 50 ° C., preferably at a temperature between ⁇ 20 ° C. and 20 ° C., the reaction product of (a) Reacting the boron reagent; (c) to the reaction mixture is then added compound (III), palladium catalyst and base, and optionally water, at a temperature between 0 ° C. and 100 ° C., preferably 0 ° C. and 40 ° C. Can be produced by reacting the reaction product of (b) with compound (III) at a temperature between
  • alkyl metal reagent examples include alkyllithium reagents such as n-butyllithium (n-BuLi), hexyllithium, and methyllithium, and alkylmagnesium such as phenyllithium, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, and butylmagnesium chloride. Examples thereof include a reagent and its lithium chloride complex.
  • the alkyl metal reagent is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (II).
  • the alkyl metal reagent used in the step (a) includes a lithium chloride complex of isopropylmagnesium chloride. preferable.
  • reaction conditions at extremely low temperatures are not required, and the reaction can be carried out at a temperature around 0 ° C. without reducing the yield.
  • Examples of the boron reagent include alkyl borate such as trimethyl borate and triisopropyl borate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-isopropoxy-4 , 4,6-trimethyl-1,3,2-dioxaborinane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like, preferably boric acid And trimethyl.
  • the boron reagent is used in an amount of, for example, 1 to 10 equivalents, preferably 2 to 4 equivalents, relative to compound (II).
  • the palladium catalyst examples include 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride-dichloromethane complex, bis (triphenylphosphine) palladium dichloride, palladium carbon, bis (tri-tert-butylphosphine) palladium, [1, 3-bis (diphenylphosphino) propane] palladium dichloride, [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium dichloride, chloro [[1,3-bis (2,6-diisopropylphenyl) Imidazol-2-ylidene] (acetanilide) palladium], [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride, and the like, preferably 1,1 And '-bis (diphenylpho
  • the base examples include metal bases such as tripotassium phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, t-butoxy potassium, cesium fluoride, and organic bases such as diisopropylethylamine and triethylamine. And tripotassium phosphate.
  • the base is used in an amount of, for example, 1 to 10 equivalents, preferably 5.5 to 6.5 equivalents, relative to compound (II).
  • Compound (III) can be obtained as a commercially available product, for example, by the method described in WO2008 / 150914 or the like, or a method analogous thereto.
  • Compound (III) is used in an amount of, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (II).
  • the organic solvent include ether solvents such as THF, 2-methyltetrahydrofuran, cyclopentylmethyl ether, t-butylmethyl ether, dioxane, aromatic hydrocarbon solvents such as toluene, 2-propanol, ethanol, methanol, butanol, and the like. These alcohol solvents are used, and these are used alone or in combination.
  • the target product can be obtained with high reproducibility and high yield by mixing water with an organic solvent.
  • compound (I) is prepared by reacting (d) compound (II) with an alkyl metal reagent and a boron reagent in an organic solvent at a temperature between ⁇ 100 ° C. and 10 ° C., and (e) Compound (III), palladium catalyst and base, and optionally water are then added to the reaction mixture, at a temperature between 0 ° C. and 100 ° C., preferably between 0 ° C. and 40 ° C. (d ) Reaction product and compound (III) can also be produced.
  • compound (I) is obtained by reacting compound (II) with an alkyl metal reagent, a boron reagent, compound (III), a palladium catalyst and a base in an organic solvent at a temperature between -100 ° C. and 10 ° C. It can also be prepared by reacting for 5 minutes to 24 hours followed by a temperature between 0 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 40 ° C.
  • the alkyl metal reagent, boron reagent, palladium catalyst, base, and organic solvent used in these different methods the same ones as described above are preferable.
  • the compound (I) obtained in this step can be decolorized and treated with activated carbon, for example, and the purity can be increased.
  • the steps (a), (b) and (c), or the steps (d) and (e) above can be carried out in one pot without the need to isolate each reaction intermediate. It is simple in terms of operation and is an excellent manufacturing method.
  • compound (I) when R 1 is tert-butyl and R 2a and R 2b are methyl, that is, when compound (I) is compound (IA), compound (IA) is obtained as a crystal. You can also The crystal of compound (IA) has different crystal forms such as type I crystal, type II crystal, etc., but as drug substance for pharmaceuticals, type II crystal is a more stable crystal. It is preferable because it can be obtained with good reproducibility.
  • the type II crystal of the compound (IA) can be produced, for example, by recrystallizing the compound (IA) obtained in the above step 3 or the like.
  • the compound (IA) is dissolved in an appropriate solvent, a poor solvent is added, the solution is cooled and crystallized, and the precipitated crystal is obtained by filtration or the like.
  • Suitable solvents to be used include, for example, ethanol, 2-propanol, ethyl acetate, acetone and the like
  • poor solvents include, for example, water, n-heptane and the like, usually 10 to 30 V / w, preferably 15 Used with a capacity of ⁇ 20 v / w.
  • This method is excellent in, for example, a high yield.
  • recrystallization with seed crystals can achieve control of crystal shape, particle shape, etc., and improvement of reproducibility.
  • the seed crystal can be obtained, for example, by crystallization without using a seed crystal by the above-described recrystallization method, and more specifically, by the method described in Example 5 or a method analogous thereto. be able to.
  • the product of each step in the above production method can also be isolated as a salt.
  • it can be purified as it is when the product of each step is obtained in the form of a salt, and when it is obtained in a free form, the product is dissolved or suspended in a suitable solvent. It may be isolated and purified by forming a salt by adding an acid or a base.
  • Examples of the salt of the product of each step in the above production method such as compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate; acetate, oxalate , Organic acid salts such as maleate, fumarate, citrate, benzoate and methanesulfonate; fluorine-substituted alkylsulfonate such as pentafluorosulfonate and nonafluorobutanesulfonate; sodium salt Alkali metal salts such as potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; zinc salts; ammonium salts such as ammonium and tetramethylammonium; organic amine addition salts such as morpholine and piperidine; Examples include amino acid addition salts such as glycine, phenylalanine, aspartic acid, and glutamic acid.
  • organic acid salts such as
  • Example 2 the reaction solution was subjected to 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid obtained in Example 1 at 2 to 5 ° C. with vigorous stirring ( A solution of 4-fluorotetrahydro-2H-pyran-4-yl) methyl (32.0 kg, 76.8 mol) dissolved in DMA (37.7 kg) was added dropwise. The reaction solution was heated to 35 ° C. and stirred at the same temperature for 2 hours. The reaction was brought to room temperature and 1-propanol (30.9 kg) was added.
  • Step 3 Under an argon atmosphere, the compound (Ic) (16.8 kg, 45.9 mol) obtained in Step 2 was dissolved in THF (149.3 kg). After cooling to 3 ° C., a 1.3 mol / L isopropyl magnesium chloride-lithium chloride complex THF solution (66.5 kg, 91.8 mol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. At 2 ° C., trimethyl borate (10.0 kg, 96.4 mol) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 1 hour.
  • reaction solution was degassed under reduced pressure, brought to room temperature, and stirred for 4 hours.
  • 6.0 mol / L hydrochloric acid (128.4 kg) was added dropwise at 14 to 15 ° C. until the pH of the reaction solution reached 1.9.
  • n-heptane (57.5 kg) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 40 ° C. or lower until the solvent could not be distilled off.
  • Activated charcoal (1.68 kg) was suspended in water (8.4 kg) and added to the residue. After stirring at room temperature for 1 hour, insoluble matters were filtered and washed with water (33.6 kg).
  • the mixture was cooled to 10 ° C. over 1 hour and stirred at the same temperature for 1 hour.
  • the obtained crystals were collected by filtration and washed with a mixed solvent of 2-propanol and water (mixing ratio 1: 5, 57.5 kg).
  • the obtained crystals were dried under reduced pressure at 60 ° C. to obtain type II crystals (13.8 kg, yield 93%) of compound (IA).
  • the mixture was cooled to 5 ° C. while gradually cooling and stirred for 2 hours, and then the resulting crystals were collected by filtration.
  • the obtained crystals were washed with a mixed solution of ethyl acetate and n-heptane (mixing ratio 1: 4, 335 mL).
  • the obtained crystals were dried under reduced pressure at 50 ° C. to obtain type II crystals (61.3 g, yield 91%) of compound (IA).
  • 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride-dichloromethane complex 837 mg, 1.02 mmol was added and degassed again.
  • the reaction solution was stirred at 30 ° C. for 2 hours, and 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride-dichloromethane complex (419 mg, 0.512 mmol) was added again and stirred at the same temperature for 24 hours.
  • the activated carbon was filtered and washed with 0.1 mol / L hydrochloric acid (38 mL), and then 10 mol / L aqueous sodium hydroxide solution (56.3 mL) was added to adjust the pH to 8.9.
  • the reaction mixture was extracted with ethyl acetate (188 mL), and the organic layer was washed with saturated brine (94 mL) and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, and ethyl acetate (19 mL) and n-heptane (75 mL) were added to the residue, followed by stirring at 60 ° C. for 1 hour and further stirring at 0 ° C. for 1 hour.
  • the precipitated solid was collected by filtration, washed successively with a mixture of ethyl acetate and n-heptane (mixing ratio 1: 4, 38 mL) and n-heptane (38 mL), and then dried under reduced pressure at 50 ° C. to give a compound (
  • the crude product of IA) (16.3 g, 41.9 mmol) was obtained.
  • Ethyl acetate (40 mL) was added to the crude product (5.00 g, 12.8 mmol) of the compound (IA) obtained here, and the mixture was heated to 65 ° C. and dissolved.

Abstract

　The present invention provides a method for producing an imidazole compound represented by formula (I) or a salt thereof, the method being characterized in comprising a step for reacting a compound represented by formula (II) or a salt thereof with an alkyl metal reagent, a boron reagent, and a compound represented by formula (III) or a salt thereof. (In the formulas, R1, R2a, and R2b are the same or different and represent lower alkyls.)

Description

イミダゾール化合物の製造方法Method for producing imidazole compound
　本発明は、イミダゾール化合物の製造方法に関する。 The present invention relates to a method for producing an imidazole compound.
　下記式 The following formula
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
(式中、R1は、置換基を有していてもよい低級アルキル等を表し、R2は、置換基を有していてもよい脂肪族複素環基等を表し、R3は、置換基を有していてもよい芳香族複素環基等を表し、nは0～3の整数を表す)で表されるイミダゾール化合物又はその薬学的に許容される塩等がカンナビノイド2型(CB2)受容体調節作用を有し、疼痛等の治療及び／又は予防剤として有用であることが知られており、例えば、式(I) (Wherein R 1 represents an optionally substituted lower alkyl or the like, R 2 represents an optionally substituted aliphatic heterocyclic group or the like, and R 3 represents a substituted Represents an aromatic heterocyclic group which may have a group, and n represents an integer of 0 to 3) or a pharmaceutically acceptable salt thereof is cannabinoid type 2 (CB2) It is known that it has a receptor-modulating action and is useful as a therapeutic and / or prophylactic agent for pain and the like, for example, the formula (I)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
(式中、R1、R2a及びR2bは、同一又は異なって低級アルキルを表す)で表されるイミダゾール化合物等が例示されている(特許文献1)。 (Wherein, R 1 , R 2a, and R 2b are the same or different and represent lower alkyl) and the like are exemplified (Patent Document 1).
　特許文献1によれば、下記スキームに従い、例えば式(IA)で表される化合物が製造できることが示されている(実施例186参照)。 According to Patent Document 1, it is shown that, for example, a compound represented by the formula (IA) can be produced according to the following scheme (see Example 186).
　即ち、(4-フルオロテトラヒドロ-2H-ピラン-4-イル)メタノール(I-a)から導かれる2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-4-ヨード-1H-イミダゾール(I-c)を、Stilleカップリング反応により6-トリブチルスタニル-2-クロロピラジンと反応させ2-(2-tert-ブチル-1-((4-フルオロテトラフドロ-2H-ピラン-4-イル)メチル)-1H-イミダゾール-4-イル)-6-クロロピラジン(I-d)を得た後、一酸化炭素挿入反応により6-(2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-1H-イミダゾール-4-イル)ピラジン-2-カルボン酸プロピル(I-e)を得、水酸化リチウムを用いて加水分解し6-(2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-1H-イミダゾール-4-イル)ピラジン-2-カルボン酸(I-f)を得た後、アミド化反応によりジメチルアミンと反応させ式(IA)で表される化合物を製造している(6工程、トータル収率22%)。 That is, 2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -4 derived from (4-fluorotetrahydro-2H-pyran-4-yl) methanol (Ia) -Iodo-1H-imidazole (Ic) was reacted with 6-tributylstannyl-2-chloropyrazine via a Stille coupling reaction to give 2- (2-tert-butyl-1-((4-fluorotetrafudo-2H After obtaining -pyran-4-yl) methyl) -1H-imidazol-4-yl) -6-chloropyrazine (Id), carbon monoxide insertion reaction was performed to give 6- (2-tert-butyl-1-(( 4-Fluorotetrahydro-2H-pyran-4-yl) methyl) -1H-imidazol-4-yl) pyrazine-2-carboxylate propyl (Ie) was obtained and hydrolyzed with lithium hydroxide to give 6- (2 -tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -1H-imidazol-4-yl) pyrazine-2-carboxylic acid (If) was obtained, followed by amidation reaction Reacts with dimethylamine It manufactures a compound represented by not formula (IA) (6 steps, 22% total yield).
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
[式中、Tfはトリフルオロメチルスルホニルを表し、Buはn-ブチルを表し、Acはアセチルを表し、dpppは1,3-ビス(ジフェニルホスフィノ)プロパンを表し、nPrはn-プロピルを表し、Meはメチルを表し、WSCは1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドを表し、HOBtは1-ヒドロキシベンゾトリアゾールを表す] [In the formula, Tf represents trifluoromethylsulfonyl, Bu represents n-butyl, Ac represents acetyl, dppp represents 1,3-bis (diphenylphosphino) propane, and n Pr represents n -propyl. And Me represents methyl, WSC represents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and HOBt represents 1-hydroxybenzotriazole]
国際公開第2008/029825号パンフレットInternational Publication No. 2008/029825 Pamphlet
　本発明の目的は、CB2受容体調節作用を有し、疼痛等の治療及び／又は予防剤として有用な式(I)で表されるイミダゾール化合物、及びその製造中間体である式(VI)で表されるテトラヒドロフラン化合物の製造方法等を提供することにある。また別の目的は、医薬品としての使用に有用な式(I)で表されるイミダゾール化合物の結晶形態を提供することにある。 An object of the present invention is an imidazole compound represented by formula (I) having a CB2 receptor modulating action and useful as a therapeutic and / or prophylactic agent for pain and the like, and formula (VI) which is an intermediate for the production thereof. It is providing the manufacturing method etc. of the tetrahydrofuran compound represented. Another object is to provide a crystalline form of the imidazole compound represented by the formula (I) useful for use as a pharmaceutical product.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
(式中、R1、R2a及びR2bは、同一又は異なって低級アルキルを表し、nは1～7の整数を表す) (Wherein R 1 , R 2a and R 2b are the same or different and represent lower alkyl, and n represents an integer of 1 to 7)
　本発明は、以下の(1)～(27)に関する。
(1) 式(II)で表される化合物又はその塩を、アルキル金属試薬、ホウ素試薬、及び式(III)で表される化合物又はその塩と反応させることを特徴とする、式(I) The present invention relates to the following (1) to (27).
(1) A compound represented by formula (II) or a salt thereof is reacted with an alkyl metal reagent, a boron reagent, and a compound represented by formula (III) or a salt thereof,
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
(式中、R1、R2a及びR2bは、同一又は異なって低級アルキルを表す)で表されるイミダゾール化合物又はその塩の製造方法。
(2) 式(II)で表される化合物又はその塩をアルキル金属試薬及びホウ素試薬と反応させ、次いで、得られる反応生成物を式(III)で表される化合物又はその塩と、パラジウム触媒及び塩基の存在下で反応させることを特徴とする、式(I) (Wherein R 1 , R 2a and R 2b are the same or different and represent lower alkyl), and a method for producing an imidazole compound or a salt thereof.
(2) A compound represented by the formula (II) or a salt thereof is reacted with an alkyl metal reagent and a boron reagent, and then the resulting reaction product is converted to a compound represented by the formula (III) or a salt thereof and a palladium catalyst. And reaction in the presence of a base, formula (I)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
(式中、R1、R2a及びR2bは、それぞれ前記と同義である)で表されるイミダゾール化合物又はその塩の製造方法。
(3) 式(II)で表される化合物又はその塩をアルキル金属試薬と反応させ、次いで、得られる反応生成物をホウ素試薬と反応させ、次いで、得られる反応生成物を式(III)で表される化合物又はその塩と、パラジウム触媒及び塩基の存在下で反応させることを特徴とする、式(I) (Wherein R 1 , R 2a and R 2b have the same meanings as described above, respectively).
(3) The compound represented by formula (II) or a salt thereof is reacted with an alkyl metal reagent, then the resulting reaction product is reacted with a boron reagent, and then the resulting reaction product is represented by formula (III) A compound represented by the formula (I), or a salt thereof, in the presence of a palladium catalyst and a base,
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
(式中、R1、R2a及びR2bは、それぞれ前記と同義である)で表されるイミダゾール化合物又はその塩の製造方法。
(4) アルキル金属試薬が、アルキルマグネシウム試薬又はその塩化リチウム複合体である(1)～(3)のいずれかに記載の製造方法。
(5) アルキル金属試薬が、イソプロピルマグネシウムクロリドの塩化リチウム複合体である(1)～(3)のいずれかに記載の製造方法。 (Wherein R 1 , R 2a and R 2b have the same meanings as described above, respectively).
(4) The production method according to any one of (1) to (3), wherein the alkyl metal reagent is an alkyl magnesium reagent or a lithium chloride complex thereof.
(5) The production method according to any one of (1) to (3), wherein the alkyl metal reagent is a lithium chloride complex of isopropylmagnesium chloride.
(6) ホウ素試薬が、ホウ酸トリメチルである(1)～(5)のいずれかに記載の製造方法。
(7) パラジウム触媒が、1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体である(1)～(6)のいずれかに記載の製造方法。
(8) 塩基が、リン酸三カリウムである(1)～(7)のいずれかに記載の製造方法。
(9) R2a及びR2bがメチルである(1)～(8)のいずれかに記載の製造方法。
(10) R1がtert-ブチルである(1)～(9)のいずれかに記載の製造方法。
(11) 式(I)で表されるイミダゾール化合物が、式(IA)  (6) The production method according to any one of (1) to (5), wherein the boron reagent is trimethyl borate.
(7) The production method according to any one of (1) to (6), wherein the palladium catalyst is 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride-dichloromethane complex.
(8) The production method according to any one of (1) to (7), wherein the base is tripotassium phosphate.
(9) The production method according to any one of (1) to (8), wherein R 2a and R 2b are methyl.
(10) The production method according to any one of (1) to (9), wherein R 1 is tert-butyl.
(11) The imidazole compound represented by the formula (I) is represented by the formula (IA)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
で表されるイミダゾール化合物である(1)～(10)のいずれかに記載の製造方法。
(12) 式(II)で表される化合物又はその塩が、
工程(i): 式(IV)で表される化合物及び式(V)で表される化合物を、塩基の存在下で反応させ、式(VI)で表される化合物を得る工程 The production method according to any one of (1) to (10), which is an imidazole compound represented by the formula:
(12) The compound represented by the formula (II) or a salt thereof is
Step (i): a step of obtaining a compound represented by the formula (VI) by reacting a compound represented by the formula (IV) and a compound represented by the formula (V) in the presence of a base.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
(式中、nは1～7の整数を表す)、及び
工程(ii): 式(VI)で表される化合物、及び式(VII)で表される化合物又はその塩を、塩基の存在下で反応させ、式(II)で表される化合物又はその塩を得る工程 (Wherein n represents an integer of 1 to 7) and step (ii): the compound represented by formula (VI) and the compound represented by formula (VII) or a salt thereof in the presence of a base. To obtain a compound represented by the formula (II) or a salt thereof
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
(式中、nは前記と同義であり、R1は低級アルキルを表す)を含む工程により得られる化合物又はその塩である(1)～(11)のいずれかに記載の製造方法。
(13) 工程(i)で用いる塩基が、トリエチルアミン、N-メチルイミダゾール、ジアザビシクロウンデカン、ジイソプロピルエチルアミン、ピリジン、N-メチルピペリジン及びモルホリンから選ばれる有機塩基である(12)記載の製造方法。
(14) 工程(i)で用いる塩基が、トリエチルアミンである(12)記載の製造方法。
(15) 工程(ii)で用いる塩基が、ヘキサメチルジシラザンリチウム、ヘキサメチルジシラザンナトリウム、ヘキサメチルジシラザンカリウム及びリチウムジイソプロピルアミドから選ばれるアルキルアミンの金属塩である(12)～(14)のいずれかに記載の製造方法。
(16) 工程(ii)で用いる塩基が、ヘキサメチルジシラザンリチウムである(12)～(14)のいずれかに記載の製造方法。
(17) nが3である(12)～(16)のいずれかに記載の製造方法。 (1) The production method according to any one of (1) to (11), wherein the compound is a compound obtained by a process comprising the step (wherein n is as defined above and R 1 represents lower alkyl) or a salt thereof.
(13) The production method according to (12), wherein the base used in step (i) is an organic base selected from triethylamine, N-methylimidazole, diazabicycloundecane, diisopropylethylamine, pyridine, N-methylpiperidine and morpholine.
(14) The production method according to (12), wherein the base used in step (i) is triethylamine.
(15) The base used in step (ii) is a metal salt of an alkylamine selected from hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium and lithium diisopropylamide (12) to (14) The manufacturing method in any one of.
(16) The production method according to any one of (12) to (14), wherein the base used in step (ii) is hexamethyldisilazane lithium.
(17) The production method according to any one of (12) to (16), wherein n is 3.
(18) 粉末X線結晶回折(Cu Kα線)において、2θ(°)が、11.2、14.7、22.7、24.0、25.9に特徴的なピークを示す式(IA) (18) In the powder X-ray crystal diffraction (Cu Kα ray), 2θ (°) shows a characteristic peak at 11.2, 14.7, 22.7, 24.0, 25.9 (IA)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
で表されるイミダゾール化合物の結晶。
(19) 粉末X線結晶回折(Cu Kα線)において、2θ(°)が、10.3、11.2、13.3、14.7、15.3、15.9、16.2、18.7、19.4、20.3、20.9、21.3、22.7、23.4、24.0、25.9、27.6、28.5及び30.3に特徴的なピークを示す式(IA) A crystal of an imidazole compound represented by:
(19) In powder X-ray crystal diffraction (Cu Kα ray), 2θ (°) is 10.3, 11.2, 13.3, 14.7, 15.3, 15.9, 16.2, 18.7, 19.4, 20.3, 20.9, 21.3, 22.7, 23.4, 24.0 , 25.9, 27.6, 28.5, and 30.3 showing the characteristic peaks (IA)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
で表されるイミダゾール化合物の結晶。
(20) 式(IA)  A crystal of an imidazole compound represented by:
(20) Formula (IA)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
で表されるイミダゾール化合物を、2-プロパノール及び水から再結晶することで得られる(18)又は(19)記載の結晶の製造方法。
(21) 式(IA)  The method for producing a crystal according to (18) or (19), which is obtained by recrystallizing an imidazole compound represented by the formula from 2-propanol and water.
(21) Formula (IA)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
で表されるイミダゾール化合物を、酢酸エチル、2-プロパノール及びn-ヘプタンから再結晶することで得られる(18)又は(19)記載の結晶の製造方法。
(22) 式(IA)  The method for producing a crystal according to (18) or (19), which is obtained by recrystallizing an imidazole compound represented by the formula from ethyl acetate, 2-propanol and n-heptane.
(22) Formula (IA)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
で表されるイミダゾール化合物を、酢酸エチル及びn-ヘプタンから再結晶することで得られる(18)又は(19)記載の結晶の製造方法。
(23) 式(IA) The method for producing a crystal according to (18) or (19), which is obtained by recrystallizing an imidazole compound represented by the formula from ethyl acetate and n-heptane.
(23) Formula (IA)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
で表されるイミダゾール化合物が、(1)～(17)のいずれかに記載の製造方法で得られるイミダゾール化合物である、(20)～(22)のいずれかに記載の結晶の製造方法。
(24) 式(VI) The method for producing a crystal according to any one of (20) to (22), wherein the imidazole compound represented by the formula (1) is an imidazole compound obtained by the production method according to any one of (1) to (17).
(24) Formula (VI)
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
(式中、nは1～7の整数を表す)で表されるテトラヒドロフラン化合物。
(25) nが3である(24)記載のテトラヒドロフラン化合物。
(26) 式(IV)で表される化合物及び式(V)で表される化合物を反応させることを特徴とする、式(VI) (Wherein n represents an integer of 1 to 7).
(25) The tetrahydrofuran compound according to (24), wherein n is 3.
(26) A compound represented by formula (VI), characterized by reacting a compound represented by formula (IV) and a compound represented by formula (V):
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
(式中、nは1～7の整数を表す)で表されるテトラヒドロフラン化合物の製造方法。
(27) nが3である(26)記載の製造方法。 (Wherein n represents an integer of 1 to 7).
(27) The production method according to (26), wherein n is 3.
　本発明により、CB2受容体調節作用を有し、疼痛等の治療及び／又は予防剤として有用な式(I)で表されるイミダゾール化合物、及びその製造中間体である式(VI)で表されるテトラヒドロフラン化合物の製造方法等が提供される。また、医薬品としての使用に有用な式(I)で表されるイミダゾール化合物の結晶形態が提供される。 According to the present invention, an imidazole compound represented by formula (I) having a CB2 receptor modulating action and useful as a therapeutic and / or prophylactic agent for pain and the like, and represented by formula (VI) which is an intermediate for the production thereof. And the like, and the like. Also provided is a crystalline form of the imidazole compound represented by formula (I) useful for use as a pharmaceutical product.
化合物(IA)のI型結晶の粉末X線結晶回折パターンを示したものである。縦軸は回折強度(カウント毎秒)、横軸は2θ(°)を表す。2 shows a powder X-ray crystal diffraction pattern of type I crystal of compound (IA). The vertical axis represents diffraction intensity (counts per second), and the horizontal axis represents 2θ (°). 化合物(IA)のII型結晶の粉末X線結晶回折パターンを示したものである。縦軸は回折強度(カウント毎秒)、横軸は2θ(°)を表す。2 shows a powder X-ray crystal diffraction pattern of a type II crystal of compound (IA). The vertical axis represents diffraction intensity (counts per second), and the horizontal axis represents 2θ (°).
　以下、式(I)で表される化合物を化合物(I)という。他の式番号の化合物についても同様である。 Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
　各化合物における各基の定義において、
　低級アルキルとしては、例えば直鎖又は分岐状の炭素数1～10のアルキルがあげられ、より具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル等があげられる。 In the definition of each group in each compound,
Examples of the lower alkyl include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Examples include isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
　次に、本発明の製造方法について説明する。なお、以下に示す製造方法において、定義した基が該製造法の条件下で変化するか、又は該製造方法を実施するのに不適切な場合、有機合成化学で常用される保護基の導入及び除去方法[例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス第4版(Protective Groups in Organic Synthesis, fourth edition）、グリーン(T.W.Greene)著、John Wiley & Sons Inc.(2006年)等に記載の方法]等を用いることにより、目的化合物を製造することができる。
製造方法1 Next, the manufacturing method of this invention is demonstrated. In addition, in the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the production method, introduction of a protective group commonly used in organic synthetic chemistry and Removal methods [e.g., Protective Groups in Organic Synthesis, fourth edition, written by TW Greene, John Wiley & Sons Inc. (2006), etc. ] Can be used to produce the target compound.
Manufacturing method 1
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
(式中、n、R1、R2a及びR2b は、それぞれ前記と同義である) Wherein n, R 1 , R 2a and R 2b are as defined above.
[工程1]
　化合物(VI)は、化合物(IV)を、有機溶媒中、塩基の存在下、-50℃と100℃の間の温度で、好ましくは0℃と20℃の間の温度で、化合物(V)と反応させることにより製造することができる。 [Process 1]
Compound (VI) is obtained by reacting Compound (IV) in an organic solvent in the presence of a base at a temperature between −50 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 20 ° C. It can manufacture by making it react.
　化合物(IV)は、例えばWO2008/029825等に記載の方法、又はそれに準じた方法により得ることができる。
　塩基としては、例えばトリエチルアミン、N-メチルイミダゾール、ジアザビシクロウンデセン(DBU)、ジイソプロピルエチルアミン、ピリジン、N-メチルピペリジン、モルホリン等の有機塩基、炭酸カリウム、炭酸カルシウム等の金属塩基等があげられる。該塩基は、化合物(IV)に対して例えば1～10当量、好ましくは1～2当量用いられる。 Compound (IV) can be obtained, for example, by the method described in WO2008 / 029825 or the like, or a method analogous thereto.
Examples of the base include organic bases such as triethylamine, N-methylimidazole, diazabicycloundecene (DBU), diisopropylethylamine, pyridine, N-methylpiperidine, morpholine, and metal bases such as potassium carbonate and calcium carbonate. . The base is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (IV).
　化合物(V)は、市販品として、もしくは例えば，文献(J. of Chem. Soc. London, 1957, p.2640-2645)等に記載の方法、又はそれに準じた方法により得ることができる。また、化合物(V)は、化合物(IV)に対して例えば1～10当量、好ましくは1～2当量用いられる。
　有機溶媒としては、例えばテトラヒドロフラン(THF)、t-ブチルメチルエーテル等のエーテル系溶媒、N,N-ジメチルホルムアミド(DMF)、N,N-ジメチルアセトアミド(DMA)、ジメチルイミダゾリジノン(DMI)、N-メチルピロリジン(NMP)等のアミド系溶媒、エチルメチルケトン等のケトン系溶媒、アセトニトリル等のニトリル系溶媒、ジメチルスルホキシド(DMSO)等があげられ、これらは単独で又は混合して用いることができる。該有機溶媒は、化合物(IV)に対して通常1～20容量/重量(v/w)、好ましくは2～8 v/wの容量で用いられる。 Compound (V) can be obtained as a commercially available product, for example, by the method described in the literature (J. of Chem. Soc. London, 1957, p.2640-2645) or the like, or a method analogous thereto. Compound (V) is used in an amount of, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (IV).
Examples of the organic solvent include ether solvents such as tetrahydrofuran (THF) and t-butyl methyl ether, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethylimidazolidinone (DMI), Examples include amide solvents such as N-methylpyrrolidine (NMP), ketone solvents such as ethyl methyl ketone, nitrile solvents such as acetonitrile, and dimethyl sulfoxide (DMSO). These may be used alone or in combination. it can. The organic solvent is generally used in a volume of 1 to 20 volume / weight (v / w), preferably 2 to 8 v / w, relative to compound (IV).
　例えば、本工程における式中のnが3である場合、用いる塩基としてはトリエチルアミン等が好ましく、用いる有機溶媒としてはTHF等が好ましい。本工程では、反応終了後、反応混合物中に例えば水等の貧溶媒を添加することで、純度よく簡便にかつ収率よく化合物(VI)を固体として析出させることができる。なお、貧溶媒の添加は、まずDMA及び水の混合溶媒(混合体積比1:1)を滴下し、続いて水を滴下することにより、穏やかに固体を析出させることができ、純度の高い化合物(IV)を取得することができる。また、化合物(VI)は安定で取り扱いが容易であり、工業的な大量合成を志向した場合、操作面において簡便であり、本製造方法は優れた製造方法である。 For example, when n in the formula in this step is 3, the base to be used is preferably triethylamine or the like, and the organic solvent to be used is preferably THF or the like. In this step, after completion of the reaction, the compound (VI) can be precipitated as a solid with good purity and ease by adding a poor solvent such as water to the reaction mixture. In addition, the addition of a poor solvent can be performed by first dropping a mixed solvent of DMA and water (mixing volume ratio 1: 1), followed by dropwise addition of water, so that a solid can be gently precipitated, and a high purity compound. (IV) can be obtained. In addition, compound (VI) is stable and easy to handle, and is convenient in terms of operation when industrial mass synthesis is intended, and this production method is an excellent production method.
[工程2]
　化合物(II)は、化合物(VI)を、有機溶媒中、塩基の存在下、-50℃と100℃の間の温度で、好ましくは0℃と40℃の間の温度で、化合物(VII)と反応させることにより製造することができる。 [Process 2]
Compound (II) is obtained by converting Compound (VI) from Compound (VII) in an organic solvent in the presence of a base at a temperature between −50 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 40 ° C. It can manufacture by making it react.
　塩基としては、例えばヘキサメチルジシラザンリチウム、ヘキサメチルジシラザンナトリウム、ヘキサメチルジシラザンカリウム、リチウムジイソプロピルアミド(LDA)等のアルキルアミンの金属塩、炭酸セシウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等の金属塩基等があげられる。該塩基は、化合物(VII)に対して例えば1～10当量、好ましくは1～2当量用いられる。 Examples of the base include metal salts of alkylamines such as hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium, lithium diisopropylamide (LDA), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. And metal bases such as lithium hydroxide. The base is used, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (VII).
　化合物(VII)は、例えばWO2008/029825等に記載の方法、又はそれに準じた方法により得ることができる。また、化合物(VI)は、化合物(VII)に対して例えば1～10当量、好ましくは1～2当量用いられる。
　有機溶媒としては、例えばTHF、t-ブチルメチルエーテル等のエーテル系溶媒、DMF、DMA、DMI、NMP等のアミド系溶媒、アセトニトリル等のニトリル系溶媒、DMSO等があげられ、これらは単独で又は混合して用いることができる。該有機溶媒は、化合物(VI)に対して通常1～20 v/w、好ましくは2～8 v/wの容量で用いられる。 Compound (VII) can be obtained, for example, by the method described in WO2008 / 029825 or the like, or a method analogous thereto. Compound (VI) is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (VII).
Examples of the organic solvent include ether solvents such as THF and t-butyl methyl ether, amide solvents such as DMF, DMA, DMI, and NMP, nitrile solvents such as acetonitrile, DMSO, and the like. It can be used by mixing. The organic solvent is generally used in a volume of 1 to 20 v / w, preferably 2 to 8 v / w, relative to compound (VI).
　例えば、本工程における式中のnが3であり、R1がtert-ブチルである場合、用いる塩基としてはヘキサメチルジシラザンリチウム等が好ましく、該塩基を選択することで反応液が均一になり、本工程の再現性を向上させることができる。また、用いる有機溶媒としてはTHF及びDMAの混合溶媒(混合体積比3:5)が好ましく、該溶媒は化合物(VII)の溶解性に優れている。本反応では、反応終了後、反応混合物を例えば塩酸等の酸で中和し、該溶媒中に例えば水等の貧溶媒を添加することで、化合物(II)を純度よく簡便にかつ収率よく固体として析出させることができる。なお、反応混合物を酸で中和する前に、反応混合物中に1-プロパノールを加えておくことにより、緩やかに固体を析出させることができ、純度の高い化合物(II)を取得することが可能となる。 For example, when n in the formula in this step is 3 and R 1 is tert-butyl, the base to be used is preferably hexamethyldisilazane lithium or the like, and the reaction solution becomes uniform by selecting the base. The reproducibility of this process can be improved. As the organic solvent to be used, a mixed solvent of THF and DMA (mixing volume ratio 3: 5) is preferable, and the solvent is excellent in solubility of the compound (VII). In this reaction, after completion of the reaction, the reaction mixture is neutralized with an acid such as hydrochloric acid, and a poor solvent such as water is added to the solvent, whereby the compound (II) is easily purified with high purity and yield. It can be deposited as a solid. In addition, by adding 1-propanol to the reaction mixture before neutralizing the reaction mixture with acid, a solid can be slowly precipitated, and a high purity compound (II) can be obtained. It becomes.
[工程3]
　化合物(I)は、(a) 化合物(II)を、有機溶媒中、-100℃と10℃の間の温度で、好ましくは-20℃と5℃の間の温度で、アルキル金属試薬と反応させ、(b) 次いで反応混合物に、ホウ素試薬を添加し、-100℃と50℃の間の温度で、好ましくは-20℃と20℃の間の温度で、(a)の反応生成物とホウ素試薬を反応させ、(c) 次いで反応混合物に、化合物(III)、パラジウム触媒及び塩基、並びに必要により水を添加し、0℃と100℃の間の温度で、好ましくは0℃と40℃の間の温度で、(b)の反応生成物と化合物(III)を反応させることにより製造することができる。 [Process 3]
Compound (I) is obtained by reacting (a) Compound (II) with an alkyl metal reagent in an organic solvent at a temperature between −100 ° C. and 10 ° C., preferably at a temperature between −20 ° C. and 5 ° C. (B) then boron reagent is added to the reaction mixture and at a temperature between −100 ° C. and 50 ° C., preferably at a temperature between −20 ° C. and 20 ° C., the reaction product of (a) Reacting the boron reagent; (c) to the reaction mixture is then added compound (III), palladium catalyst and base, and optionally water, at a temperature between 0 ° C. and 100 ° C., preferably 0 ° C. and 40 ° C. Can be produced by reacting the reaction product of (b) with compound (III) at a temperature between
　アルキル金属試薬としては、例えばn-ブチルリチウム(n-BuLi)、ヘキシルリチウム、メチルリチウム等のアルキルリチウム試薬、フェニルリチウム、イソプロピルマグネシウムクロリド、メチルマグネシウムクロリド、エチルマグネシウムクロリド、ブチルマグネシウムクロリド等のアルキルマグネシウム試薬及びその塩化リチウム複合体等があげられる。該アルキル金属試薬は、化合物(II)に対して例えば1～10当量、好ましくは1～2当量用いられる。例えば、本工程における式中のR1がtert-ブチルであり、R2a及びR2bがメチルである場合、(a)の段階で用いるアルキル金属試薬としてはイソプロピルマグネシウムクロリドの塩化リチウム複合体等が好ましい。該アルキル金属試薬を用いることで、極低温での反応条件を必要とせず、0℃付近の温度でも収率を低下させることなく反応を行うことができる。 Examples of the alkyl metal reagent include alkyllithium reagents such as n-butyllithium (n-BuLi), hexyllithium, and methyllithium, and alkylmagnesium such as phenyllithium, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, and butylmagnesium chloride. Examples thereof include a reagent and its lithium chloride complex. The alkyl metal reagent is used, for example, in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (II). For example, when R 1 in the formula in this step is tert-butyl and R 2a and R 2b are methyl, the alkyl metal reagent used in the step (a) includes a lithium chloride complex of isopropylmagnesium chloride. preferable. By using the alkyl metal reagent, reaction conditions at extremely low temperatures are not required, and the reaction can be carried out at a temperature around 0 ° C. without reducing the yield.
　ホウ素試薬としては、例えばホウ酸トリメチル、ホウ酸トリイソプロピル等のホウ酸アルキル、2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン、2-イソプロポキシ-4,4,6-トリメチル-1,3,2-ジオキサボリナン、2-メトキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン等の環状ホウ素試薬があげられ、好ましくはホウ酸トリメチル等があげられる。該ホウ素試薬は、化合物(II)に対して例えば1～10当量、好ましくは2～4当量用いられる。 Examples of the boron reagent include alkyl borate such as trimethyl borate and triisopropyl borate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-isopropoxy-4 , 4,6-trimethyl-1,3,2-dioxaborinane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like, preferably boric acid And trimethyl. The boron reagent is used in an amount of, for example, 1 to 10 equivalents, preferably 2 to 4 equivalents, relative to compound (II).
　パラジウム触媒としては、例えば1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体、ビス(トリフェニルホスフィン)パラジウムジクロリド、パラジウム炭素、ビス(トリ-tert-ブチルホスフィン)パラジウム、[1,3-ビス(ジフェニルホスフィノ)プロパン]パラジウムジクロリド、[1,1'-ビス(ジ-tert-ブチルホスフィノ)フェロセン]パラジウムジクロリド、クロロ[[1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン](アセトアニリド)パラジウム]、[1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン](3-クロロピリジル)パラジウムジクロリド等があげられ、好ましくは1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体等があげられる。該パラジウム触媒は、化合物(II)に対して例えば0.001～1当量用いられる。 Examples of the palladium catalyst include 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride-dichloromethane complex, bis (triphenylphosphine) palladium dichloride, palladium carbon, bis (tri-tert-butylphosphine) palladium, [1, 3-bis (diphenylphosphino) propane] palladium dichloride, [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium dichloride, chloro [[1,3-bis (2,6-diisopropylphenyl) Imidazol-2-ylidene] (acetanilide) palladium], [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium dichloride, and the like, preferably 1,1 And '-bis (diphenylphosphino) ferrocenepalladium dichloride-dichloromethane complex. The palladium catalyst is used, for example, in an amount of 0.001 to 1 equivalent relative to compound (II).
　塩基としては、例えば、リン酸三カリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、t-ブトキシカリウム、セシウムフルオリド等の金属塩基、ジイソプロピルエチルアミン、トリエチルアミン等の有機塩基等があげられ、好ましくは、リン酸三カリウム等があげられる。該塩基は、化合物(II)に対して例えば1～10当量、好ましくは5.5～6.5当量用いられる。なお、該塩基を添加する際は、例えば水等に溶解させてゆっくりと滴下することで、発熱を抑制し、収率よく化合物(I)を取得することが可能となる。 Examples of the base include metal bases such as tripotassium phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, t-butoxy potassium, cesium fluoride, and organic bases such as diisopropylethylamine and triethylamine. And tripotassium phosphate. The base is used in an amount of, for example, 1 to 10 equivalents, preferably 5.5 to 6.5 equivalents, relative to compound (II). In addition, when adding the base, for example, it is possible to obtain compound (I) with high yield by suppressing exotherm by dissolving it in water or the like and slowly dropping it.
　化合物(III)は、市販品として、又は例えばWO2008/150914等に記載の方法、もしくはそれに準じた方法により得ることができる。また、化合物(III)は、化合物(II)に対して例えば1～10当量、好ましくは1～2当量用いられる。
　有機溶媒としては、例えばTHF、2-メチルテトラヒドロフラン、シクロペンチルメチルエーテル、t-ブチルメチルエーテル、ジオキサン等のエーテル系溶媒、トルエン等の芳香族炭化水素系溶媒、2-プロパノール、エタノール、メタノール、ブタノール等のアルコール系溶媒等があげられ、これらは単独で又は混合して用いられる。好ましくはTHF等があげられ、該溶媒は化合物(II)の溶解性に優れている。また、(c)の段階においては、塩基として例えばリン酸三カリウム等の金属塩基を用いる場合、有機溶媒に水を混合すると、再現性良く高収率で目的物を取得することができる。 Compound (III) can be obtained as a commercially available product, for example, by the method described in WO2008 / 150914 or the like, or a method analogous thereto. Compound (III) is used in an amount of, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (II).
Examples of the organic solvent include ether solvents such as THF, 2-methyltetrahydrofuran, cyclopentylmethyl ether, t-butylmethyl ether, dioxane, aromatic hydrocarbon solvents such as toluene, 2-propanol, ethanol, methanol, butanol, and the like. These alcohol solvents are used, and these are used alone or in combination. Preferred is THF, and the solvent is excellent in the solubility of the compound (II). In the step (c), when a metal base such as tripotassium phosphate is used as the base, the target product can be obtained with high reproducibility and high yield by mixing water with an organic solvent.
　また、別法として、化合物(I)は、(d) 化合物(II)を、有機溶媒中、-100℃と10℃の間の温度で、アルキル金属試薬及びホウ素試薬と反応させ、(e) 次いで、反応混合物に、化合物(III)、パラジウム触媒及び塩基、並びに必要により水を添加し、0℃と100℃の間の温度で、好ましくは0℃と40℃の間の温度で、(d)の反応生成物と化合物(III)を反応させることにより製造することもできる。 Alternatively, compound (I) is prepared by reacting (d) compound (II) with an alkyl metal reagent and a boron reagent in an organic solvent at a temperature between −100 ° C. and 10 ° C., and (e) Compound (III), palladium catalyst and base, and optionally water are then added to the reaction mixture, at a temperature between 0 ° C. and 100 ° C., preferably between 0 ° C. and 40 ° C. (d ) Reaction product and compound (III) can also be produced.
　さらに別法として、化合物(I)は、化合物(II)を、アルキル金属試薬、ホウ素試薬、化合物(III)、パラジウム触媒及び塩基と、有機溶媒中、-100℃と10℃の間の温度で5分間～24時間、続いて0℃と100℃の間の温度で、好ましくは0℃と40℃の間の温度で、反応させることにより製造することもできる。
　これら別法で用いるアルキル金属試薬、ホウ素試薬、パラジウム触媒、塩基、及び有機溶媒としては、前記と同じものが好ましい。 As a further alternative, compound (I) is obtained by reacting compound (II) with an alkyl metal reagent, a boron reagent, compound (III), a palladium catalyst and a base in an organic solvent at a temperature between -100 ° C. and 10 ° C. It can also be prepared by reacting for 5 minutes to 24 hours followed by a temperature between 0 ° C. and 100 ° C., preferably at a temperature between 0 ° C. and 40 ° C.
As the alkyl metal reagent, boron reagent, palladium catalyst, base, and organic solvent used in these different methods, the same ones as described above are preferable.
　本工程で得られる化合物(I)は、必要により、例えば活性炭で処理することで、脱色等ができ、純度をあげることができる。
　上記(a)、(b)及び(c)の段階、又は上記(d)及び(e)の段階は、それぞれの反応中間体を単離する必要が無く、ワンポットで実施することができるため、操作面において簡便であり、優れた製造方法である。 If necessary, the compound (I) obtained in this step can be decolorized and treated with activated carbon, for example, and the purity can be increased.
The steps (a), (b) and (c), or the steps (d) and (e) above can be carried out in one pot without the need to isolate each reaction intermediate. It is simple in terms of operation and is an excellent manufacturing method.
　化合物(I)のうち、R1がtert-ブチルであり、R2a及びR2bがメチルである場合、すなわち、化合物(I)が化合物(IA)である場合、化合物(IA)は結晶として取得することもできる。化合物(IA)の結晶は、I型結晶、II型結晶等の異なる結晶形が存在するが、医薬品の原薬としては、II型結晶の方がより安定な結晶であり、以下に示す方法により、再現性よく取得できるため好ましい。 Among compounds (I), when R 1 is tert-butyl and R 2a and R 2b are methyl, that is, when compound (I) is compound (IA), compound (IA) is obtained as a crystal. You can also The crystal of compound (IA) has different crystal forms such as type I crystal, type II crystal, etc., but as drug substance for pharmaceuticals, type II crystal is a more stable crystal. It is preferable because it can be obtained with good reproducibility.
　該化合物(IA)のII型結晶は、例えば上記工程3等で得られる化合物(IA)を再結晶することにより製造することができる。再結晶は、化合物(IA)を適当な溶媒に溶解した後、貧溶媒を加え、冷却晶析させ、析出した結晶をろ過等により取得すればよい。用いる適当な溶媒としては、例えばエタノール、2-プロパノール、酢酸エチル、アセトン等があげられ、貧溶媒としては、例えば水、n-ヘプタン等があげられ、通常10～30 v/w、好ましくは15～20 v/wの容量で用いられる。中でも、化合物(IA)を2-プロパノール及び水の混合溶媒(混合体積比1:5)に加熱溶解させた後、種晶及び水を加えて冷却晶析させ、析出した結晶をろ取する方法が好ましい。該方法は、例えば収率が高い点等が優れている。また、種晶を加えて再結晶を行うことにより、結晶形、粒子形等のコントロール、及び再現性の向上を達成することができる。該種晶は、例えば上記の再結晶の方法で、種晶を使用せずに結晶化することにより得ることができ、より具体的には実施例5記載の方法、又はそれに準じた方法により得ることができる。 The type II crystal of the compound (IA) can be produced, for example, by recrystallizing the compound (IA) obtained in the above step 3 or the like. For recrystallization, the compound (IA) is dissolved in an appropriate solvent, a poor solvent is added, the solution is cooled and crystallized, and the precipitated crystal is obtained by filtration or the like. Suitable solvents to be used include, for example, ethanol, 2-propanol, ethyl acetate, acetone and the like, and poor solvents include, for example, water, n-heptane and the like, usually 10 to 30 V / w, preferably 15 Used with a capacity of ~ 20 v / w. Among them, a method in which compound (IA) is heated and dissolved in a mixed solvent of 2-propanol and water (mixing volume ratio 1: 5), then seed crystals and water are added to cool crystallization, and the precipitated crystals are collected by filtration. Is preferred. This method is excellent in, for example, a high yield. In addition, recrystallization with seed crystals can achieve control of crystal shape, particle shape, etc., and improvement of reproducibility. The seed crystal can be obtained, for example, by crystallization without using a seed crystal by the above-described recrystallization method, and more specifically, by the method described in Example 5 or a method analogous thereto. be able to.
　上記の製造方法における各工程の生成物は、塩として単離することもできる。該塩を取得したいとき、各工程の生成物が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、該生成物を適当な溶媒に溶解又は懸濁し、酸又は塩基を加えることにより塩を形成させて単離、精製すればよい。 The product of each step in the above production method can also be isolated as a salt. When it is desired to obtain the salt, it can be purified as it is when the product of each step is obtained in the form of a salt, and when it is obtained in a free form, the product is dissolved or suspended in a suitable solvent. It may be isolated and purified by forming a salt by adding an acid or a base.
　化合物(I)等上記の製造方法における各工程の生成物の塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩；酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、安息香酸塩、メタンスルホン酸塩等の有機酸塩；ペンタフルオロスルホン酸塩、ノナフルオロブタンスルホン酸塩等のフッ素置換アルキルスルホン酸塩；ナトリウム塩、カリウム塩等のアルカリ金属塩；マグネシウム塩、カルシウム塩等のアルカリ土類金属塩；アルミニウム塩；亜鉛塩；アンモニウム、テトラメチルアンモニウム等のアンモニウム塩；モルホリン、ピペリジン等の有機アミン付加塩；リジン、グリシン、フェニルアラニン、アスパラギン酸、グルタミン酸等のアミノ酸付加塩があげられる。 Examples of the salt of the product of each step in the above production method such as compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate; acetate, oxalate , Organic acid salts such as maleate, fumarate, citrate, benzoate and methanesulfonate; fluorine-substituted alkylsulfonate such as pentafluorosulfonate and nonafluorobutanesulfonate; sodium salt Alkali metal salts such as potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; zinc salts; ammonium salts such as ammonium and tetramethylammonium; organic amine addition salts such as morpholine and piperidine; Examples include amino acid addition salts such as glycine, phenylalanine, aspartic acid, and glutamic acid.
　以下、本発明を実施例、及び参考例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。
　なお、実施例及び参考例で用いられるプロトン核磁気共鳴スペクトル(1H NMR)は、270 MHz又は300 MHzで測定されたものであり、化合物及び測定条件によって交換性プロトンが明瞭には観測されないことがある。なお、シグナルの多重度の表記としては通常用いられるものを用いる。また、各化合物の命名にはChemBioDraw Ultra Ver.11.0を用いた。 EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further more concretely, the scope of the present invention is not limited to these Examples.
The proton nuclear magnetic resonance spectrum ( 1 H NMR) used in Examples and Reference Examples is measured at 270 MHz or 300 MHz, and exchangeable protons are not clearly observed depending on the compound and measurement conditions. There is. In addition, what is usually used is used as the notation of the multiplicity of signals. Moreover, ChemBioDraw Ultra Ver.11.0 was used for naming each compound.
1,1,2,2,3,3,4,4,4-ノナフルオロブタン-1-スルホン酸(4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチルの製造
　窒素雰囲気下、WO2006/034093に記載の方法で得られる(4-フルオロテトラヒドロ-2H-ピラン-4-イル)メタノール(化合物(I-a))(32.0 kg、239 mol)をTHF(142 kg)に溶解し、5℃に冷却した。0～10℃で、トリエチルアミン(38.2 kg、378 mol)及び1,1,2,2,3,3,4,4,4-ノナフルオロブタンスルホニルフルオリド(90.7 kg、300 mol)を順次滴下して加えた。滴下終了後、反応液を0～10℃で2時間撹拌し、同温度でDMA(152 kg)及び水(160 kg)の混合液を滴下した。滴下終了後、反応液を室温にし、水(320 kg)を滴下した。滴下終了後、反応液を室温で1時間撹拌した後、0℃に冷却し、同温度で1時間撹拌した。析出した固体をろ取し、THF(24 kg)及び水(240 kg)の混合溶媒で洗浄した。得られた固体を減圧下乾燥して、1,1,2,2,3,3,4,4,4-ノナフルオロブタン-1-スルホン酸(4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル(67.5 kg、収率68%)を得た。
1H-NMR (CDCl3, δ, ppm): 4.48 (d, J = 19.1 Hz, 2H), 3.91-3.87 (m, 2H), 3.79-3.70 (m, 2H), 1.92-1.66 (m, 4H). Preparation of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid (4-fluorotetrahydro-2H-pyran-4-yl) methyl under nitrogen atmosphere, WO2006 / 034093 (4-fluorotetrahydro-2H-pyran-4-yl) methanol (compound (Ia)) (32.0 kg, 239 mol) obtained by the method described in 1) was dissolved in THF (142 kg) and cooled to 5 ° C. . At 0-10 ° C, triethylamine (38.2 kg, 378 mol) and 1,1,2,2,3,3,4,4,4-nonafluorobutanesulfonyl fluoride (90.7 kg, 300 mol) were added dropwise. Added. After completion of the dropwise addition, the reaction solution was stirred at 0 to 10 ° C. for 2 hours, and a mixed solution of DMA (152 kg) and water (160 kg) was added dropwise at the same temperature. After completion of the dropping, the reaction solution was brought to room temperature and water (320 kg) was added dropwise. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, cooled to 0 ° C., and stirred at the same temperature for 1 hour. The precipitated solid was collected by filtration and washed with a mixed solvent of THF (24 kg) and water (240 kg). The obtained solid was dried under reduced pressure to obtain 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid (4-fluorotetrahydro-2H-pyran-4-yl ) Methyl (67.5 kg, 68% yield) was obtained.
1 H-NMR (CDCl 3 , δ, ppm): 4.48 (d, J = 19.1 Hz, 2H), 3.91-3.87 (m, 2H), 3.79-3.70 (m, 2H), 1.92-1.66 (m, 4H ).
6-(2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-1H-イミダゾール-4-イル)-N,N-ジメチルピラジン-2-カルボキサミド(化合物(IA))の製造
(工程1)
　窒素雰囲気下、室温で、WO2008/029825に記載の方法で得られる2-tert-ブチル-4-ヨード-1H-イミダゾール(16.0 kg、64.0 mol)をDMA(82.9 kg)に溶解させた。5℃で撹拌下、1.0 mol/L ヘキサメチルジシラザンリチウム THF溶液(68.4 kg、76.8 mol)を滴下した。続いて、反応液を強撹拌下、2～5℃で、実施例1で得られた1,1,2,2,3,3,4,4,4-ノナフルオロブタン-1-スルホン酸(4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル(32.0 kg、76.8 mol)をDMA(37.7 kg)に溶解した溶液を滴下した。反応液を35℃に昇温し、同温度で2時間撹拌した。反応液を室温にし、1-プロパノール(30.9 kg)を加えた。さらに、反応液のpHが7.5になるまで、1.0 mol/L 塩酸(97.2 kg)を滴下した後、水(134.7 kg)を滴下した。反応液を室温で1時間撹拌した後、10℃に冷却し、同温度で1時間撹拌した。析出した固体をろ取し、1-プロパノール及び水の混合液(混合比1:10、94.2 kg)で洗浄した。得られた固体を60℃で減圧乾燥して、2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-4-ヨード-1H-イミダゾールの粗生成物(19.2 kg、収率82%)を得た。 6- (2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -1H-imidazol-4-yl) -N, N-dimethylpyrazine-2-carboxamide (compound (IA))
(Process 1)
2-tert-butyl-4-iodo-1H-imidazole (16.0 kg, 64.0 mol) obtained by the method described in WO2008 / 029825 was dissolved in DMA (82.9 kg) at room temperature under a nitrogen atmosphere. While stirring at 5 ° C., 1.0 mol / L hexamethyldisilazane lithium THF solution (68.4 kg, 76.8 mol) was added dropwise. Subsequently, the reaction solution was subjected to 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid obtained in Example 1 at 2 to 5 ° C. with vigorous stirring ( A solution of 4-fluorotetrahydro-2H-pyran-4-yl) methyl (32.0 kg, 76.8 mol) dissolved in DMA (37.7 kg) was added dropwise. The reaction solution was heated to 35 ° C. and stirred at the same temperature for 2 hours. The reaction was brought to room temperature and 1-propanol (30.9 kg) was added. Furthermore, 1.0 mol / L hydrochloric acid (97.2 kg) was added dropwise until the pH of the reaction solution reached 7.5, and then water (134.7 kg) was added dropwise. The reaction solution was stirred at room temperature for 1 hour, then cooled to 10 ° C., and stirred at the same temperature for 1 hour. The precipitated solid was collected by filtration and washed with a mixed solution of 1-propanol and water (mixing ratio 1:10, 94.2 kg). The obtained solid was dried at 60 ° C. under reduced pressure to give a crude product of 2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -4-iodo-1H-imidazole (19.2 kg, yield 82%) was obtained.
(工程2)
　工程1で得られた2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-4-ヨード-1H-イミダゾールの粗生成物(18.7 kg、51.1 mol)に、DMA(93.5 kg)及びTHF(33.2 kg)を加え、室温で撹拌して溶解した。不溶物をろ過して、THF(19.9 kg)で洗浄した(得られたろ液をろ液-Aと呼ぶ)。1-プロパノール(24.1 kg)及び水(180.0 kg)の混合液を室温で撹拌し、ろ液-Aを0.5時間かけて滴下し、1時間撹拌した。これを10℃に冷却し、1時間撹拌した。析出した固体をろ取し、水(94.0 kg)で洗浄した。得られた固体を80℃で減圧乾燥して、2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-4-ヨード-1H-イミダゾール(化合物(I-c))(17.6 kg、収率94%)を得た。
1H-NMR (CDCl3, δ, ppm): 7.17 (d, J = 1.7 Hz, 1H), 4.21 (d, J = 23.7 Hz, 2H), 3.90-3.84 (m, 2H), 3.71 (td, J = 11.1, 3.2 Hz, 2H), 1.79-1.59 (m, 4H), 1.41 (s, 9H). (Process 2)
Crude product of 2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -4-iodo-1H-imidazole obtained in step 1 (18.7 kg, 51.1 mol) DMA (93.5 kg) and THF (33.2 kg) were added thereto, and dissolved by stirring at room temperature. The insoluble material was filtered and washed with THF (19.9 kg) (the resulting filtrate is referred to as filtrate-A). A mixture of 1-propanol (24.1 kg) and water (180.0 kg) was stirred at room temperature, and filtrate-A was added dropwise over 0.5 hours, followed by stirring for 1 hour. This was cooled to 10 ° C. and stirred for 1 hour. The precipitated solid was collected by filtration and washed with water (94.0 kg). The obtained solid was dried at 80 ° C. under reduced pressure to give 2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -4-iodo-1H-imidazole (compound (Ic )) (17.6 kg, 94% yield).
1 H-NMR (CDCl 3 , δ, ppm): 7.17 (d, J = 1.7 Hz, 1H), 4.21 (d, J = 23.7 Hz, 2H), 3.90-3.84 (m, 2H), 3.71 (td, J = 11.1, 3.2 Hz, 2H), 1.79-1.59 (m, 4H), 1.41 (s, 9H).
(工程3)
　アルゴン雰囲気下、工程2で得られた化合物(I-c)(16.8 kg、45.9 mol)をTHF(149.3 kg)に溶解した。3℃に冷却後、1.3 mol/Lイソプロピルマグネシウムクロリドの塩化リチウム複合体THF溶液(66.5 kg、91.8 mol)を滴下し、同温度で2時間撹拌した。2℃で、反応液にホウ酸トリメチル(10.0 kg、96.4 mol)を滴下し、同温度で1時間撹拌した。同温度で、反応液に、WO2008/150914に記載の方法で得られる6-クロロ-N,N-ジメチルピラジン-2-カルボキサミド(9.37 kg、50.5 mol)、1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体(187 g、229 mmol)及びTHF(14.9 kg)を加え、同温度で強撹拌下、水(67.2 kg)、続いてリン酸三カリウム(58.4 kg、275 mol)を水(100.8 kg)に溶解した溶液を、2.5時間かけて順に滴下した。滴下終了後、反応液を減圧で脱気した後、室温にし、4時間撹拌した。反応液に、6.0 mol/L 塩酸(128.4 kg)を、反応液のpHが1.9となるまで14～15℃で滴下した。滴下終了後、反応液にn-ヘプタン(57.5 kg)を加え、40℃以下で、溶媒が留去しなくなるまで減圧濃縮した。残渣に、活性炭(1.68 kg)を水(8.4 kg)に懸濁して加え、室温で1時間撹拌した後、不溶物をろ過し、水(33.6 kg)で洗浄した。得られたろ液に酢酸エチル(75.8 kg)を加え、13～19℃で水相のpHが7.5となるまで10 mol/L 水酸化ナトリウム水溶液(66.0 kg)を強撹拌下で滴下した。滴下終了後、反応液に酢酸エチル(151.5 kg)を加え、50℃で1時間撹拌した。同温度で反応液をろ過した後、酢酸エチル(75.9 kg)で洗浄した。ろ液を50～60℃で0.5時間撹拌した後、界面がはっきりするまで静置し、有機相と水相とに分けた。得られた水相に酢酸エチル(151.5 kg)を加えて35℃で抽出した。有機相を合併し、40℃以下で残渣が約84 Lになるまで溶媒を減圧濃縮した後、実施例5で得られる種晶(16.8 g)、及びn-ヘプタン(114.9 kg)を加え、40℃以下で残渣が約84 Lになるまで溶媒を減圧濃縮した。濃縮残渣にn-ヘプタン(114.9 kg)を加え、40℃以下で残渣が101～118 Lになるまで溶媒を減圧濃縮した。濃縮残渣に2-プロパノール(13.2 kg)を加え、60℃に昇温し、1時間撹拌した。続いて反応液を1時間かけて30℃に冷却し、その後、1時間かけて10℃に冷却し、同温度で1時間撹拌した。析出した結晶をろ取し、2-プロパノール及びn-ヘプタンの混合液(混合比1:10、46.6 kg)で洗浄した。得られた結晶を50℃で減圧乾燥して、化合物(IA)の粗生成物(II型結晶)(15.7 kg、収率88%)を得た。 (Process 3)
Under an argon atmosphere, the compound (Ic) (16.8 kg, 45.9 mol) obtained in Step 2 was dissolved in THF (149.3 kg). After cooling to 3 ° C., a 1.3 mol / L isopropyl magnesium chloride-lithium chloride complex THF solution (66.5 kg, 91.8 mol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. At 2 ° C., trimethyl borate (10.0 kg, 96.4 mol) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. At the same temperature, 6-chloro-N, N-dimethylpyrazine-2-carboxamide (9.37 kg, 50.5 mol), 1,1′-bis (diphenylphosphino) obtained by the method described in WO2008 / 150914 was added to the reaction solution. ) Ferrocene palladium dichloride-dichloromethane complex (187 g, 229 mmol) and THF (14.9 kg) were added, and water (67.2 kg) was added under vigorous stirring at the same temperature, followed by tripotassium phosphate (58.4 kg, 275 mol). A solution dissolved in water (100.8 kg) was sequentially added dropwise over 2.5 hours. After completion of the dropwise addition, the reaction solution was degassed under reduced pressure, brought to room temperature, and stirred for 4 hours. To the reaction solution, 6.0 mol / L hydrochloric acid (128.4 kg) was added dropwise at 14 to 15 ° C. until the pH of the reaction solution reached 1.9. After completion of the dropwise addition, n-heptane (57.5 kg) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 40 ° C. or lower until the solvent could not be distilled off. Activated charcoal (1.68 kg) was suspended in water (8.4 kg) and added to the residue. After stirring at room temperature for 1 hour, insoluble matters were filtered and washed with water (33.6 kg). Ethyl acetate (75.8 kg) was added to the obtained filtrate, and 10 mol / L aqueous sodium hydroxide solution (66.0 kg) was added dropwise with vigorous stirring until the pH of the aqueous phase reached 7.5 at 13-19 ° C. After completion of the dropwise addition, ethyl acetate (151.5 kg) was added to the reaction solution and stirred at 50 ° C. for 1 hour. The reaction mixture was filtered at the same temperature and washed with ethyl acetate (75.9 kg). The filtrate was stirred at 50-60 ° C. for 0.5 hour, then allowed to stand until the interface was clear, and separated into an organic phase and an aqueous phase. Ethyl acetate (151.5 kg) was added to the obtained aqueous phase and extracted at 35 ° C. The organic phases were combined, and the solvent was concentrated under reduced pressure at 40 ° C. or lower until the residue was about 84 L, and then the seed crystals (16.8 g) obtained in Example 5 and n-heptane (114.9 kg) were added, and 40 The solvent was concentrated under reduced pressure until the residue was about 84 L below ℃. N-Heptane (114.9 kg) was added to the concentrated residue, and the solvent was concentrated under reduced pressure at 40 ° C. or lower until the residue became 101 to 118 L. 2-Propanol (13.2 kg) was added to the concentrated residue, the temperature was raised to 60 ° C., and the mixture was stirred for 1 hour. Subsequently, the reaction solution was cooled to 30 ° C. over 1 hour, then cooled to 10 ° C. over 1 hour, and stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and washed with a mixed solution of 2-propanol and n-heptane (mixing ratio 1:10, 46.6 kg). The obtained crystals were dried at 50 ° C. under reduced pressure to obtain a crude product of compound (IA) (type II crystals) (15.7 kg, yield 88%).
　実施例2の工程3で得られた化合物(IA)の粗生成物(14.9 kg、38.3 mol)に、水(37.3 kg)及び2-プロパノール(29.2 kg)を加え、67℃で加熱撹拌し、溶解した。67℃で熱時ろ過した後、2-プロパノール(5.8 kg)及び水(7.5 kg)の混合溶媒で洗浄した。ろ液を62℃まで昇温し、同温度で水(134.1 kg)を滴下した。63℃で、実施例5で得られる種晶(14.9 g)を加え、1時間撹拌した後、同温度のまま、水(44.7 kg)を滴下し、1時間撹拌した。この混合液を1時間かけて10℃に冷却し、同温度で1時間撹拌した。得られた結晶をろ取し、2-プロパノール及び水の混合溶媒(混合比1:5、57.5 kg)で洗浄した。得られた結晶を60℃で減圧乾燥して、化合物(IA)のII型結晶(13.8 kg、収率93%)を得た。
1H-NMR (CDCl3, δ, ppm)：9.24 (s, 1H), 8.67 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 4.30 (d, J = 23.5 Hz, 2H), 3.91-3.85 (m, 2H), 3.73 (td, J = 11.2, 3.1 Hz, 2H), 3.17 (s, 3H), 3.13 (s, 3H), 1.89-1.66 (m, 4H), 1.49 (s, 9H).
融点：165℃
粉末X線結晶回折(Cu Kα線)における特徴的なピーク(2θ(°))：10.3、11.2、13.3、14.7、15.3、15.9、16.2、18.7、19.4、20.3、20.9、21.3、22.7、23.4、24.0、25.9、27.6、28.5、30.3
　また、実施例4の方法を用いても化合物(IA)のII型結晶を得ることができる。 Water (37.3 kg) and 2-propanol (29.2 kg) were added to the crude product (14.9 kg, 38.3 mol) of compound (IA) obtained in step 3 of Example 2, and the mixture was heated and stirred at 67 ° C. Dissolved. After hot filtration at 67 ° C., the mixture was washed with a mixed solvent of 2-propanol (5.8 kg) and water (7.5 kg). The filtrate was heated to 62 ° C., and water (134.1 kg) was added dropwise at the same temperature. The seed crystal (14.9 g) obtained in Example 5 was added at 63 ° C. and stirred for 1 hour, and then water (44.7 kg) was added dropwise at the same temperature, followed by stirring for 1 hour. The mixture was cooled to 10 ° C. over 1 hour and stirred at the same temperature for 1 hour. The obtained crystals were collected by filtration and washed with a mixed solvent of 2-propanol and water (mixing ratio 1: 5, 57.5 kg). The obtained crystals were dried under reduced pressure at 60 ° C. to obtain type II crystals (13.8 kg, yield 93%) of compound (IA).
1 H-NMR (CDCl 3 , δ, ppm): 9.24 (s, 1H), 8.67 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 4.30 (d, J = 23.5 Hz, 2H) , 3.91-3.85 (m, 2H), 3.73 (td, J = 11.2, 3.1 Hz, 2H), 3.17 (s, 3H), 3.13 (s, 3H), 1.89-1.66 (m, 4H), 1.49 (s , 9H).
Melting point: 165 ° C
Characteristic peak (2θ (°)) in powder X-ray crystal diffraction (Cu Kα ray): 10.3, 11.2, 13.3, 14.7, 15.3, 15.9, 16.2, 18.7, 19.4, 20.3, 20.9, 21.3, 22.7, 23.4, 24.0, 25.9, 27.6, 28.5, 30.3
Further, the type II crystal of compound (IA) can also be obtained by using the method of Example 4.
　実施例2の工程3で得られる化合物(IA)の粗生成物(67.0 g、172 mmol)に、酢酸エチル(268 mL)及び2-プロパノール(134 mL)を加え、60℃で加熱撹拌し、溶解した。この溶液に活性炭(2 g)を加え、0.5時間撹拌した後、熱時ろ過し、残渣を酢酸エチル(134 mL)で洗浄した。ろ液を40℃まで徐冷して0.5時間撹拌した後、実施例5で得られる種晶を加えた。これを同温度でさらに1時間撹拌した後、n-ヘプタン(1.07 L)を1時間かけて滴下した。これを徐冷しながら5℃まで冷却し、2時間撹拌した後、得られた結晶をろ取した。得られた結晶を酢酸エチル及びn-ヘプタンの混合液(混合比1：4、335 mL)で洗浄した。得られた結晶を50℃で減圧乾燥して、化合物(IA)のII型結晶(61.3 g、収率91%)を得た。 To the crude product of compound (IA) obtained in Step 3 of Example 2 (67.0 g, 172 mmol), ethyl acetate (268 mL) and 2-propanol (134 mL) were added, and the mixture was heated and stirred at 60 ° C. Dissolved. Activated carbon (2 g) was added to this solution, stirred for 0.5 hour, filtered while hot, and the residue was washed with ethyl acetate (134) mL). The filtrate was gradually cooled to 40 ° C. and stirred for 0.5 hour, and then the seed crystal obtained in Example 5 was added. This was further stirred at the same temperature for 1 hour, and n-heptane (1.07 L) was added dropwise over 1 hour. The mixture was cooled to 5 ° C. while gradually cooling and stirred for 2 hours, and then the resulting crystals were collected by filtration. The obtained crystals were washed with a mixed solution of ethyl acetate and n-heptane (mixing ratio 1: 4, 335 mL). The obtained crystals were dried under reduced pressure at 50 ° C. to obtain type II crystals (61.3 g, yield 91%) of compound (IA).
6-(2-tert-ブチル-1-((4-フルオロテトラヒドロ-2H-ピラン-4-イル)メチル)-1H-イミダゾール-4-イル)-N,N-ジメチルピラジン-2-カルボキサミド(化合物(IA))の種晶となるII型結晶の製造
　実施例2の工程2で得られる化合物(I-c)(18.8 g、51.2 mmol)をTHF(375 mL)に溶解した。アルゴン雰囲気下-78℃に冷却し、1.6 mol/L n-BuLiヘキサン溶液(38.4 mL、61.4 mmol)及びホウ酸トリメチル(6.9 g、66.6 mmol)を順に加えた。反応混合物を0℃に冷却し、1時間撹拌後、WO2008/150914に記載の方法で得られる6-クロロ-N,N-ジメチルピラジン-2-カルボキサミド(10.5 g、56.3 mmol)、水(36.9 mL)及びリン酸三カリウム(54.4 g、256 mmol)を加えた。反応液を脱気した後、1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体(837 mg、1.02 mmol)を加え、再度、脱気した。反応液を30℃で2時間撹拌後、再度、1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体(419 mg、0.512 mmol)を加え、同温度で24時間撹拌した。反応液に水(375 mL)を加え、濃縮した後、酢酸エチル(188 mL)及び濃塩酸(50 mL)を順次加え、pH 2.0に調整した。得られた溶液を分液し、有機層-Aと水層-Aを得た。有機層-Aをさらに0.1 mol/L塩酸(94 mL)で2回抽出し、各々水層-B及び水層-Cを得た。水層-A、水層-B及び水層-Cを合併し、活性炭(1.88 g)を加え、40℃で0.5時間撹拌した。活性炭をろ過し、0.1 mol/L塩酸(38 mL)で洗浄した後、10 mol/L 水酸化ナトリウム水溶液(56.3 mL)を加え、pH 8.9とした。反応液を酢酸エチル(188 mL)で抽出し、有機層を飽和食塩水(94 mL)で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、残渣に酢酸エチル(19 mL)及びn-ヘプタン(75 mL)を加え、60℃で1時間撹拌し、さらに0℃で1時間撹拌した。析出した固体をろ取し、酢酸エチル及びn-ヘプタンの混合液(混合比1：4、38 mL)及びn-ヘプタン(38 mL)で順次洗浄した後、50℃で減圧乾燥し、化合物(IA)の粗生成物(16.3 g、41.9 mmol)を得た。ここで得られた化合物(IA)の粗生成物(5.00 g、12.8 mmol)に酢酸エチル(40 mL)を加え、65℃に加熱し、溶解した。この溶液を40℃に冷却し、起晶を確認した後、同温度でn-ヘプタン(80 mL)を1時間かけて滴下した。その後、1時間かけて室温まで冷却し、さらに4℃まで冷却した後、1時間撹拌した。生じた結晶をろ取し、酢酸エチル及びn-ヘプタンの混合液(混合比1：4、25 mL)及びn-ヘプタン(5 mL)で順次、洗浄した後、60℃で減圧乾燥し、化合物(IA)のII型結晶(4.53 g、収率74%)を得た。該結晶を種晶として用いた。 6- (2-tert-butyl-1-((4-fluorotetrahydro-2H-pyran-4-yl) methyl) -1H-imidazol-4-yl) -N, N-dimethylpyrazine-2-carboxamide (compound Production of Type II Crystal as Seed Crystal of (IA)) Compound (Ic) (18.8 g, 51.2 mmol) obtained in Step 2 of Example 2 was dissolved in THF (375 mL). The mixture was cooled to −78 ° C. under an argon atmosphere, and 1.6 mol / L n-BuLi hexane solution (38.4 mL, 61.4 mmol) and trimethyl borate (6.9 g, 66.6 mmol) were sequentially added. The reaction mixture was cooled to 0 ° C. and stirred for 1 hour, and then 6-chloro-N, N-dimethylpyrazine-2-carboxamide (10.5 g, 56.3 mmol), water (36.9 mL) obtained by the method described in WO2008 / 150914 ) And tripotassium phosphate (54.4 g, 256 mmol). After degassing the reaction solution, 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride-dichloromethane complex (837 mg, 1.02 mmol) was added and degassed again. The reaction solution was stirred at 30 ° C. for 2 hours, and 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride-dichloromethane complex (419 mg, 0.512 mmol) was added again and stirred at the same temperature for 24 hours. Water (375 mL) was added to the reaction mixture, and the mixture was concentrated, and ethyl acetate (188 mL) and concentrated hydrochloric acid (50 mL) were successively added to adjust to pH 2.0. The obtained solution was separated to obtain an organic layer-A and an aqueous layer-A. Organic layer-A was further extracted twice with 0.1 mol / L hydrochloric acid (94 mL) to obtain aqueous layer-B and aqueous layer-C, respectively. Aqueous layer-A, aqueous layer-B and aqueous layer-C were combined, activated carbon (1.88 g) was added, and the mixture was stirred at 40 ° C. for 0.5 hr. The activated carbon was filtered and washed with 0.1 mol / L hydrochloric acid (38 mL), and then 10 mol / L aqueous sodium hydroxide solution (56.3 mL) was added to adjust the pH to 8.9. The reaction mixture was extracted with ethyl acetate (188 mL), and the organic layer was washed with saturated brine (94 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate (19 mL) and n-heptane (75 mL) were added to the residue, followed by stirring at 60 ° C. for 1 hour and further stirring at 0 ° C. for 1 hour. The precipitated solid was collected by filtration, washed successively with a mixture of ethyl acetate and n-heptane (mixing ratio 1: 4, 38 mL) and n-heptane (38 mL), and then dried under reduced pressure at 50 ° C. to give a compound ( The crude product of IA) (16.3 g, 41.9 mmol) was obtained. Ethyl acetate (40 mL) was added to the crude product (5.00 g, 12.8 mmol) of the compound (IA) obtained here, and the mixture was heated to 65 ° C. and dissolved. The solution was cooled to 40 ° C., and after crystallization was confirmed, n-heptane (80 mL) was added dropwise at the same temperature over 1 hour. Thereafter, the mixture was cooled to room temperature over 1 hour, further cooled to 4 ° C., and stirred for 1 hour. The resulting crystals were collected by filtration, washed successively with a mixture of ethyl acetate and n-heptane (mixing ratio 1: 4, 25 mL) and n-heptane (5 mL), and then dried under reduced pressure at 60 ° C. A type II crystal of (IA) (4.53 g, yield 74%) was obtained. The crystal was used as a seed crystal.
[参考例1]
　WO2008/029825の実施例186に記載の方法で得られる化合物(IA)(0.48 g, 1.2 mmol)をtert-ブチルメチルエーテル(1 mL)に溶解した。溶解後、すぐに固体が析出し懸濁液となった。懸濁液にtert-ブチルメチルエーテル(3 mL)を加え、50℃で5分間撹拌した後、室温で30分間撹拌した。生じた結晶をろ取し、化合物(IA)のI型結晶(0.32 g、収率66%)を得た。
融点：145℃
粉末X線結晶回折(Cu Kα線)における特徴的なピーク(2θ(°))：9.2、9.9、10.5、12.6、12.8、13.1、13.3、15.5、15.9、16.2、16.8、17.3、17.5、17.6、17.8、18.4、18.6、18.8、19.4、19.5、19.7、20.4、20.6、21.0、21.3、21.5、22.2、28.0、28.6、30.1 [Reference Example 1]
Compound (IA) (0.48 g, 1.2 mmol) obtained by the method described in Example 186 of WO2008 / 029825 was dissolved in tert-butyl methyl ether (1 mL). Immediately after dissolution, a solid precipitated and became a suspension. To the suspension was added tert-butyl methyl ether (3 mL), and the mixture was stirred at 50 ° C. for 5 minutes, and then stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration to obtain type I crystals (0.32 g, yield 66%) of compound (IA).
Melting point: 145 ° C
Characteristic peak (2θ (°)) in powder X-ray crystal diffraction (Cu Kα ray): 9.2, 9.9, 10.5, 12.6, 12.8, 13.1, 13.3, 15.5, 15.9, 16.2, 16.8, 17.3, 17.5, 17.6, 17.8, 18.4, 18.6, 18.8, 19.4, 19.5, 19.7, 20.4, 20.6, 21.0, 21.3, 21.5, 22.2, 28.0, 28.6, 30.1
　本発明により、CB2受容体調節作用を有し、疼痛等の治療及び／又は予防剤として有用な式(I)で表されるイミダゾール化合物、及びその製造中間体である式(VI)で表されるテトラヒドロフラン化合物の製造方法等が提供される。また、医薬品としての使用に有用な式(I)で表されるイミダゾール化合物の結晶形態が提供される。 According to the present invention, an imidazole compound represented by formula (I) having a CB2 receptor modulating action and useful as a therapeutic and / or prophylactic agent for pain and the like, and represented by formula (VI) which is an intermediate for the production thereof. And the like, and the like. Also provided is a crystalline form of the imidazole compound represented by formula (I) useful for use as a pharmaceutical product.

Claims (26)

  1. 式(II)で表される化合物又はその塩を、アルキル金属試薬、ホウ素試薬、及び式(III)で表される化合物又はその塩と反応させることを特徴とする、式(I)
    Figure JPOXMLDOC01-appb-C000001
     (式中、R1、R2a及びR2bは、同一又は異なって低級アルキルを表す)で表されるイミダゾール化合物又はその塩の製造方法。     A compound represented by formula (II) or a salt thereof is reacted with an alkyl metal reagent, a boron reagent, and a compound represented by formula (III) or a salt thereof,
    Figure JPOXMLDOC01-appb-C000001
     (Wherein R 1 , R 2a and R 2b are the same or different and represent lower alkyl), and a method for producing an imidazole compound or a salt thereof.
  2. 式(II)で表される化合物又はその塩をアルキル金属試薬及びホウ素試薬と反応させ、次いで、得られる反応生成物を式(III)で表される化合物又はその塩と、パラジウム触媒及び塩基の存在下で反応させることを特徴とする
    Figure JPOXMLDOC01-appb-C000002
     (式中、R1、R2a及びR2bは、それぞれ前記と同義である)、請求項1記載の製造方法。     A compound represented by the formula (II) or a salt thereof is reacted with an alkyl metal reagent and a boron reagent, and then the resulting reaction product is converted into a compound represented by the formula (III) or a salt thereof, a palladium catalyst and a base. Characterized by reacting in the presence
    Figure JPOXMLDOC01-appb-C000002
     2. The production method according to claim 1, wherein R 1 , R 2a and R 2b are as defined above.
  3. 式(II)で表される化合物又はその塩をアルキル金属試薬と反応させ、次いで、得られる反応生成物をホウ素試薬と反応させ、次いで、得られる反応生成物を式(III)で表される化合物又はその塩と、パラジウム触媒及び塩基の存在下で反応させることを特徴とする
    Figure JPOXMLDOC01-appb-C000003
     (式中、R1、R2a及びR2bは、それぞれ前記と同義である)、請求項1記載の製造方法。     The compound represented by the formula (II) or a salt thereof is reacted with an alkyl metal reagent, then the resulting reaction product is reacted with a boron reagent, and then the resulting reaction product is represented by the formula (III) It is characterized by reacting a compound or a salt thereof in the presence of a palladium catalyst and a base.
    Figure JPOXMLDOC01-appb-C000003
     2. The production method according to claim 1, wherein R 1 , R 2a and R 2b are as defined above.
  4. アルキル金属試薬が、アルキルマグネシウム試薬又はその塩化リチウム複合体である請求項1～3のいずれかに記載の製造方法。 4. The production method according to claim 1, wherein the alkyl metal reagent is an alkyl magnesium reagent or a lithium chloride complex thereof.
  5. アルキル金属試薬が、イソプロピルマグネシウムクロリドの塩化リチウム複合体である請求項1～3のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 3, wherein the alkyl metal reagent is a lithium chloride complex of isopropylmagnesium chloride.
  6. ホウ素試薬が、ホウ酸トリメチルである請求項1～5のいずれかに記載の製造方法。 6. The production method according to claim 1, wherein the boron reagent is trimethyl borate.
  7. パラジウム触媒が、1,1'-ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド-ジクロロメタン錯体である請求項1～6のいずれかに記載の製造方法。 7. The production method according to claim 1, wherein the palladium catalyst is 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride-dichloromethane complex.
  8. 塩基が、リン酸三カリウムである請求項1～7のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 7, wherein the base is tripotassium phosphate.
  9. R2a及びR2bがメチルである請求項1～8のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 8, wherein R 2a and R 2b are methyl.
  10. R1がtert-ブチルである請求項1～9のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 9, wherein R 1 is tert-butyl.
  11. 式(I)で表されるイミダゾール化合物が、式(IA) 
    Figure JPOXMLDOC01-appb-C000004
     で表されるイミダゾール化合物である請求項1～10のいずれかに記載の製造方法。     The imidazole compound represented by the formula (I) is represented by the formula (IA)
    Figure JPOXMLDOC01-appb-C000004
     The production method according to any one of claims 1 to 10, which is an imidazole compound represented by the formula:
  12. 式(II)で表される化合物又はその塩が、
    工程(i): 式(IV)で表される化合物及び式(V)で表される化合物を、塩基の存在下で反応させ、式(VI)で表される化合物を得る工程
    Figure JPOXMLDOC01-appb-C000005
     (式中、nは1～7の整数を表す)、及び
    工程(ii): 式(VI)で表される化合物、及び式(VII)で表される化合物又はその塩を、塩基の存在下で反応させ、式(II)で表される化合物又はその塩を得る工程
    Figure JPOXMLDOC01-appb-C000006
     (式中、nは前記と同義であり、R1は低級アルキルを表す)を含む工程により得られる化合物又はその塩である請求項1～11のいずれかに記載の製造方法。     The compound represented by the formula (II) or a salt thereof is
    Step (i): a step of obtaining a compound represented by the formula (VI) by reacting a compound represented by the formula (IV) and a compound represented by the formula (V) in the presence of a base.
    Figure JPOXMLDOC01-appb-C000005
     (Wherein n represents an integer of 1 to 7) and step (ii): the compound represented by formula (VI) and the compound represented by formula (VII) or a salt thereof in the presence of a base. To obtain a compound represented by the formula (II) or a salt thereof
    Figure JPOXMLDOC01-appb-C000006
     The production method according to any one of claims 1 to 11, which is a compound or a salt thereof obtained by a step comprising (wherein n is as defined above, and R 1 represents lower alkyl).
  13. 工程(i)で用いる塩基が、トリエチルアミン、N-メチルイミダゾール、ジアザビシクロウンデカン、ジイソプロピルエチルアミン、ピリジン、N-メチルピペリジン及びモルホリンから選ばれる有機塩基である請求項12記載の製造方法。 13. The production method according to claim 12, wherein the base used in step (i) is an organic base selected from triethylamine, N-methylimidazole, diazabicycloundecane, diisopropylethylamine, pyridine, N-methylpiperidine and morpholine.
  14. 工程(i)で用いる塩基が、トリエチルアミンである請求項12記載の製造方法。 13. The production method according to claim 12, wherein the base used in step (i) is triethylamine.
  15. 工程(ii)で用いる塩基が、ヘキサメチルジシラザンリチウム、ヘキサメチルジシラザンナトリウム、ヘキサメチルジシラザンカリウム及びリチウムジイソプロピルアミドから選ばれるアルキルアミンの金属塩である請求項12～14のいずれかに記載の製造方法。 The base used in step (ii) is a metal salt of an alkylamine selected from hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium, and lithium diisopropylamide. Manufacturing method.
  16. 工程(ii)で用いる塩基が、ヘキサメチルジシラザンリチウムである請求項12～14のいずれかに記載の製造方法。 The production method according to any one of claims 12 to 14, wherein the base used in step (ii) is hexamethyldisilazane lithium.
  17. nが3である請求項12～16のいずれかに記載の製造方法。 The production method according to any one of claims 12 to 16, wherein n is 3.
  18. 粉末X線結晶回折(Cu Kα線)において、2θ(°)が、11.2、14.7、22.7、24.0、25.9に特徴的なピークを示す式(IA)
    Figure JPOXMLDOC01-appb-C000007
     で表されるイミダゾール化合物の結晶。     In powder X-ray crystal diffraction (Cu Kα ray), 2θ (°) shows a characteristic peak at 11.2, 14.7, 22.7, 24.0, 25.9 (IA)
    Figure JPOXMLDOC01-appb-C000007
     A crystal of an imidazole compound represented by:
  19. 式(IA) 
    Figure JPOXMLDOC01-appb-C000008
     で表されるイミダゾール化合物を、2-プロパノール及び水から再結晶することで得られる請求項18記載の結晶の製造方法。     Formula (IA)
    Figure JPOXMLDOC01-appb-C000008
     19. The method for producing a crystal according to claim 18, which is obtained by recrystallizing an imidazole compound represented by the formula from 2-propanol and water.
  20. 式(IA) 
    Figure JPOXMLDOC01-appb-C000009
     で表されるイミダゾール化合物を、酢酸エチル、2-プロパノール及びn-ヘプタンから再結晶することで得られる請求項18記載の結晶の製造方法。     Formula (IA)
    Figure JPOXMLDOC01-appb-C000009
     19. The method for producing a crystal according to claim 18, which is obtained by recrystallizing an imidazole compound represented by the formula from ethyl acetate, 2-propanol and n-heptane.
  21. 式(IA) 
    Figure JPOXMLDOC01-appb-C000010
     で表されるイミダゾール化合物を、酢酸エチル及びn-ヘプタンから再結晶することで得られる請求項18記載の結晶の製造方法。     Formula (IA)
    Figure JPOXMLDOC01-appb-C000010
     19. The method for producing a crystal according to claim 18, which is obtained by recrystallizing an imidazole compound represented by the formula from ethyl acetate and n-heptane.
  22. 式(IA)
    Figure JPOXMLDOC01-appb-C000011
     で表されるイミダゾール化合物が、請求項1～17のいずれかに記載の製造方法で得られるイミダゾール化合物である、請求項19～21のいずれかに記載の結晶の製造方法。     Formula (IA)
    Figure JPOXMLDOC01-appb-C000011
     The method for producing a crystal according to any one of claims 19 to 21, wherein the imidazole compound represented by the formula is an imidazole compound obtained by the production method according to any one of claims 1 to 17.
  23. 式(VI)
    Figure JPOXMLDOC01-appb-C000012
     (式中、nは1～7の整数を表す)で表されるテトラヒドロフラン化合物。     Formula (VI)
    Figure JPOXMLDOC01-appb-C000012
     (Wherein n represents an integer of 1 to 7).
  24. nが3である請求項23記載のテトラヒドロフラン化合物。 24. The tetrahydrofuran compound according to claim 23, wherein n is 3.
  25. 式(IV)で表される化合物及び式(V)で表される化合物を反応させることを特徴とする、式(VI)
    Figure JPOXMLDOC01-appb-C000013
     (式中、nは1～7の整数を表す)で表されるテトラヒドロフラン化合物の製造方法。     Characterized by reacting a compound represented by formula (IV) and a compound represented by formula (V):
    Figure JPOXMLDOC01-appb-C000013
     (Wherein n represents an integer of 1 to 7).
  26. nが3である請求項25記載の製造方法。 26. The production method according to claim 25, wherein n is 3.
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