WO2018074566A1 - Method for producing pyrrolidine compound - Google Patents

Method for producing pyrrolidine compound Download PDF

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WO2018074566A1
WO2018074566A1 PCT/JP2017/037921 JP2017037921W WO2018074566A1 WO 2018074566 A1 WO2018074566 A1 WO 2018074566A1 JP 2017037921 W JP2017037921 W JP 2017037921W WO 2018074566 A1 WO2018074566 A1 WO 2018074566A1
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compound
formula
production method
salt
compound represented
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PCT/JP2017/037921
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孝之 愛宕
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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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Definitions

  • the present invention relates to a method for producing a pyrrolidine compound or a salt thereof.
  • R 1 and R 2 represent linear or branched alkenyl having 12 to 24 carbon atoms, etc., X 1 and X 2 together represent a single bond, etc., and is X 3 absent? , Alkyl having 1 to 6 carbon atoms, Y is absent or an anion, a and b represent 0 to 3, L 3 represents a single bond, and R 3 represents 1 to 6 carbon atoms. the alkyl or the like, pyrrolidine compound or a salt thereof represented by L 1 and L 2 represents a -O-CO-, etc.), a lipid nanoparticles that facilitates the introduction of a nucleic acid into intracellular like Known as cationic lipids to make up, for example, formula (I)
  • R 1 represents C 1-6 alkyl and R 2 represents C 12-24 alkyl or C 12-24 alkenyl
  • Patent Documents 1 and 2). are exemplified.
  • An object of the present invention is to provide an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.
  • the present invention relates to the following (1) to (13).
  • R 1 represents C 1-6 alkyl
  • R 2 represents C 12-24 alkyl or C 12-24 alkenyl
  • X represents a hydroxy or chlorine atom
  • a pyrrolidine compound represented by the formula (I) is represented by the formula (IA):
  • the present invention provides an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.
  • C 1-6 alkyl includes, for example, linear or branched alkyl having 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl and the like;
  • Examples of the C 12-24 alkyl include linear or branched alkyl having 12 to 24 carbon atoms, specifically, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3, 7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15 -Tetramethylhexadecyl, henicosyl, docosyl, tricosyl, tetracosyl etc .;
  • C 12-24 alkenyl includes, for example, linear or branched alkenyl having 12 to 24 carbon atoms containing 1 to 3 double bonds, specifically, (Z) -tridec-8-enyl, ( (Z) -tetradec-9-enyl, (Z) -pentadeca-8-enyl, (Z) -hexadeca-9-enyl, (Z) -heptadeca-5-enyl, (Z) -octadeca-6-enyl, (Z) -heptadeca-8-enyl, (Z) -octadeca-9-enyl, (E) -heptadeca-8-enyl, (E) -octadeca-9-enyl, (Z) -heptadeca-10-enyl, ( Z) -octadeca-11-enyl, (8Z, 11Z) -heptadeca-8,11-dienyl
  • Compound (IV) can be obtained by reacting Compound (V) and Compound (VI) in the presence of a formaldehyde reagent and, if necessary, Molecular Sieves 4A in an appropriate solvent.
  • the amount of compound (VI) to be used is not particularly limited, but is, for example, 1.2 to 1.5 equivalents relative to compound (V).
  • the formaldehyde reagent is not particularly limited, and examples thereof include formaldehyde and paraformaldehyde, with paraformaldehyde being preferred.
  • the amount of formaldehyde reagent used is not particularly limited, but is, for example, 1.2 to 1.5 equivalents relative to compound (V).
  • a reagent that generates formaldehyde in the reaction system may be used. Oxidation of methanol with copper (II) oxide or platinum in the reaction system generates formaldehyde (e.g. Bulletin de la Societe Chimique de France, 29, 1903, p.939-943, Angelwandte Chemie, International Edition, 51 (32), 2012, p.7985-7989 etc.).
  • the amount of molecular sieves 4A used is not particularly limited, but is, for example, 25 to 35 wt% with respect to compound (V).
  • the solvent examples include, but are not limited to, ether solvents such as tetrahydrofuran (THF); amide solvents such as N, N-dimethylacetamide; halogen solvents such as dichloromethane; aromatic hydrocarbons such as toluene and xylene; methanol, ethanol and the like.
  • An alcohol solvent etc. are mention
  • a preferred solvent is toluene.
  • the amount of the solvent to be used is not particularly limited, but it is, for example, 2 to 50 volume / weight (v / w), preferably 5 to 20 v / w, relative to compound (V).
  • the reaction is preferably carried out at a temperature between 70 ° C. and 110 ° C., more preferably at a temperature between 90 ° C. and 100 ° C., usually for 5 minutes to 72 hours, preferably 30 minutes to 4 hours.
  • Compound (V) can be obtained as a commercially available product or according to a known method (for example, The Journal of Organic Chemistry, 44 (7), 1979, pp. 1149-1154, etc.) or a method analogous thereto.
  • Compound (VI) can be obtained as a commercially available product or according to a known method (for example, WO2001 / 092208 etc.) or a method analogous thereto.
  • Process 2
  • Compound (II) can be obtained by treating compound (IV) with a reducing agent in an appropriate solvent.
  • the reducing agent is not particularly limited, and examples thereof include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, lithium borohydride and the like.
  • the amount of the reducing agent to be used is not particularly limited, but is, for example, 1.1 to 15 equivalents relative to compound (IV).
  • Lithium aluminum hydride is preferable as a reducing agent in this reaction because it has high reactivity and can proceed with a small excess equivalent to the compound (IV).
  • lithium aluminum hydride is used as the reducing agent, it is preferably used in an amount of 1.1 to 1.5 equivalents, more preferably 1.2 to 1.4 equivalents, relative to compound (IV).
  • the solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol; ether solvents such as THF; aromatic hydrocarbons such as toluene and xylene, and these are used alone or in combination.
  • a preferred solvent is THF.
  • the amount of the solvent to be used is not particularly limited, but is, for example, 2 to 50 volume / weight (v / w), preferably 10 to 20 v / w, relative to compound (IV).
  • the reaction is preferably performed at a temperature between 0 ° C. and 100 ° C., more preferably at a temperature between 20 ° C. and 50 ° C., usually for 5 minutes to 72 hours, preferably 30 minutes to 4 hours.
  • Compound (I) can be obtained by reacting Compound (II) and Compound (III) in the presence of a base.
  • compound (I) When X is hydroxy in compound (III), compound (I) is obtained by reacting compound (II) and compound (III) in the presence of a base and an additive in a suitable solvent. It is done.
  • each reagent used is not particularly limited, but with respect to compound (II), compound (III) is, for example, 2.0 to 5.0 equivalents, preferably 2.0 to 2.2 equivalents, and the base is, for example, 4.0 to 8.0 equivalents, preferably 5.5 to 6.5 equivalents and additives are, for example, 1.6 to 2.6 equivalents, preferably 2.0 to 2.2 equivalents.
  • the solvent is not particularly limited, and examples thereof include nitrile solvents such as acetonitrile; ether solvents such as THF and 2-methyltetrahydrofuran, and these are used alone or in combination.
  • a preferred solvent is acetonitrile.
  • the amount of the solvent to be used is not particularly limited, but is, for example, 2 to 100 volume / weight (v / w), preferably 5 to 30 v / w, relative to compound (II).
  • the base is not particularly limited, and examples thereof include N-methylimidazole, triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, and the like, and preferably N-methylimidazole.
  • the additive is not particularly limited, and examples thereof include p-toluenesulfonic acid chloride and carbonyldiimidazole (CDI), and p-toluenesulfonic acid chloride is preferable.
  • the reaction is preferably carried out at a temperature between ⁇ 10 ° C. and 80 ° C., more preferably at a temperature between 0 ° C. and 10 ° C., usually for 5 minutes to 72 hours, preferably 1 hour to 5 hours.
  • the compound (III) in which X is hydroxy can be obtained as a commercially available product or according to a known method (for example, Tetrahedron Letters, 49 (22), 2008, pp. 3600-3603) or a similar method.
  • the compound (I) when X is a chlorine atom, the compound (I) can be obtained by reacting the compound (II) and the compound (III) in the presence of a base in an appropriate solvent.
  • each reagent used is not particularly limited, but with respect to compound (II), compound (III) is, for example, 1.6 to 2.6 equivalents, preferably 2.0 to 2.2 equivalents, and the base is, for example, 4.0 to 8.0 equivalents, preferably 4.5 to 5.5 equivalents.
  • the solvent examples include, but are not limited to, ether solvents such as THF; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate and the like. These may be used alone or in combination.
  • a preferred solvent is acetonitrile.
  • the amount of the solvent to be used is not particularly limited, but is, for example, 2 to 100 volume / weight (v / w), preferably 10 to 30 v / w, relative to compound (II).
  • the base is not particularly limited, and examples thereof include dipropylethylamine, N-methylimidazole, triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, and the like, and preferably pyridine.
  • the reaction is preferably carried out at a temperature between 0 ° C. and 80 ° C., more preferably at a temperature between 20 ° C. and 50 ° C., usually for 5 minutes to 72 hours, preferably 1 hour to 5 hours.
  • the compound (III) in which X is a chlorine atom can be obtained as a commercially available product or according to a known method (for example, Bioorganic & Medicinal & Chemistry & Letters, 13 (12), 2003, p. 1977-1980, etc.) be able to.
  • Products and intermediates in each of the above steps should be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can do.
  • the products and intermediates in each step can be used for the next reaction without any particular purification.
  • Some intermediates and products obtained in each step may have stereoisomers such as geometric isomers and optical isomers, tautomers, etc., but the intermediates and products in the present invention Includes all possible isomers, including these, and mixtures thereof.
  • the raw material compound used in each step, the obtained intermediate and product may be in the form of a salt or a solvate.
  • the intermediate and product obtained in each step can be purified as they are, or obtained in a free form.
  • the intermediate and product obtained in each step are dissolved or suspended in a suitable solvent, and an acid or base is added to form a salt, which may be isolated and purified.
  • the starting compound used in each step, the resulting intermediate and the product salt include, for example, acid addition salts and the like.
  • the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, Examples thereof include organic acid salts such as benzoate and methanesulfonate.
  • compound (I) can be easily obtained in a shorter process than known methods (for example, WO2011 / 136368).
  • the method for synthesizing the raw materials for pharmaceuticals reduces the amount of impurities mixed in, and the production method can produce compound (I) efficiently with a certain quality with good reproducibility. It is suitable as a method.
  • the proton nuclear magnetic resonance spectrum ( 1 H NMR) used in Examples is measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, what is usually used is used as the notation of the multiplicity of signals.
  • powdered molecular sieve 4A (27.0 g) is suspended in toluene (630 ml), and at room temperature, diethyl fumarate (90.0 g, 0.52 mol), N-methylglycine (60.5 g, 0.68 mol), Paraformaldehyde (23.5 g, 0.78 mol) and toluene (270 mL) were added, followed by stirring at 90 ° C for 2 hours.
  • the reaction mixture was cooled to 60 ° C., water (270 mL) was added, and the mixture was cooled to room temperature.
  • the reaction mixture was filtered and washed with toluene (180 mL).
  • N-Heptane (290 mL) and activated carbon (870 mL) were added to the obtained product, and the mixture was stirred at 40 ° C. for 0.5 hour, and then the mixture was filtered and washed with n-heptane (100 mL).
  • the solvent of the obtained filtrate was distilled off under reduced pressure to obtain Compound (IA) (27.8 g, yield 52.8%).
  • the present invention provides an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The present invention provides an efficient production method for industrial mass synthesis of a pyrrolidine compound represented by formula (I) or a salt thereof, the method comprising reacting a compound represented by formula (II) or a salt thereof and a compound represented by formula (III) in the presence of a base.

Description

ピロリジン化合物の製造方法Method for producing pyrrolidine compound
　本発明は、ピロリジン化合物又はその塩の製造方法等に関する。 The present invention relates to a method for producing a pyrrolidine compound or a salt thereof.
　下記式 The following formula
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
(式中、R1及びR2は炭素数12～24の直鎖状もしくは分岐状のアルケニル等を表し、X1及びX2は一緒になって単結合等を表し、X3は存在しないか、炭素数1～6のアルキル等であり、Yは存在しないか、陰イオンであり、a及びbは0～3を表し、L3は単結合等を表し、R3は炭素数1～6のアルキル等を表し、L1及びL2は-O-CO-等を表す)で表されるピロリジン化合物又はその塩等は、核酸を細胞内等に導入することを容易にする脂質ナノ粒子を構成するためのカチオン性脂質として知られており、例えば式(I) (In the formula, R 1 and R 2 represent linear or branched alkenyl having 12 to 24 carbon atoms, etc., X 1 and X 2 together represent a single bond, etc., and is X 3 absent? , Alkyl having 1 to 6 carbon atoms, Y is absent or an anion, a and b represent 0 to 3, L 3 represents a single bond, and R 3 represents 1 to 6 carbon atoms. the alkyl or the like, pyrrolidine compound or a salt thereof represented by L 1 and L 2 represents a -O-CO-, etc.), a lipid nanoparticles that facilitates the introduction of a nucleic acid into intracellular like Known as cationic lipids to make up, for example, formula (I)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
(式中、R1はC1-6アルキルを表し、R2はC12-24アルキル又はC12-24アルケニルを表す)で表されるピロリジン化合物等が例示されている(特許文献1、2)。 (In the formula, R 1 represents C 1-6 alkyl and R 2 represents C 12-24 alkyl or C 12-24 alkenyl) and the like are exemplified (Patent Documents 1 and 2). ).
　例えば式(IA)で表されるピロリジン化合物の製造方法としては、例えば下記の製造方法が知られている(特許文献1の実施例110参照)。 For example, as a method for producing a pyrrolidine compound represented by the formula (IA), for example, the following production method is known (see Example 110 of Patent Document 1).
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
(式中、OEtはエトキシを表し、Bnはベンジルを表し、Bocはtert-ブトキシカルボニルを表し、DCCはジシクロヘキシルカルボジイミドを表し、DMAPは4-ジメチルアミノピリジンを表し、TFAはトリフルオロ酢酸を表し、NaBH(OAc)3はナトリウムトリアセトキシボロヒドリドを表す) (Where OEt represents ethoxy, Bn represents benzyl, Boc represents tert-butoxycarbonyl, DCC represents dicyclohexylcarbodiimide, DMAP represents 4-dimethylaminopyridine, TFA represents trifluoroacetic acid, NaBH (OAc) 3 represents sodium triacetoxyborohydride)
国際公開第2011/136368号International Publication No. 2011/136368 国際公開第2013/089152号International Publication No.2013 / 089152
　本発明の目的は、ピロリジン化合物又はその塩の工業的な大量合成を志向した効率的な製造方法等を提供することにある。 An object of the present invention is to provide an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.
　例えばWO2011/136368等に記載されている方法では、工程数も多く、操作も煩雑であるため、工業的な大量合成を志向した製造方法には不向きであり、その改善が求められる。 For example, the method described in WO2011 / 136368 etc. has many steps and is complicated in operation, and thus is unsuitable for a production method aimed at industrial mass synthesis, and its improvement is required.
　本発明は、以下の(1)～(13)に関する。 The present invention relates to the following (1) to (13).
(1) 式(II)で表される化合物又はその塩を、塩基の存在下、式(III)で表される化合物と反応させる、式(I)： (1) A compound represented by Formula (II) or a salt thereof is reacted with a compound represented by Formula (III) in the presence of a base, Formula (I):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
(式中、R1はC1-6アルキルを表し、R2はC12-24アルキル又はC12-24アルケニルを表し、Xはヒドロキシ又は塩素原子を表す)で表されるピロリジン化合物又はその塩の製造方法。 (Wherein R 1 represents C 1-6 alkyl, R 2 represents C 12-24 alkyl or C 12-24 alkenyl, and X represents a hydroxy or chlorine atom) or a salt thereof Manufacturing method.
(2) R1がメチルである(1)に記載の製造方法。 (2) The production method according to (1), wherein R 1 is methyl.
(3) R2がC12-24アルケニルである(1)又は(2)に記載の製造方法。 (3) The production method according to (1) or (2), wherein R 2 is C 12-24 alkenyl.
(4) R2がヘプタデカジエニルである(1)又は(2)に記載の製造方法。 (4) The production method according to (1) or (2), wherein R 2 is heptadecadienyl.
(5) R2が(8Z,11Z)-ヘプタデカ-8,11-ジエニルである(1)又は(2)に記載の製造方法。 (5) The production method according to (1) or (2), wherein R 2 is (8Z, 11Z) -heptadeca-8,11-dienyl.
(6) Xがヒドロキシである(1)～(5)のいずれかに記載の製造方法。 (6) The production method according to any one of (1) to (5), wherein X is hydroxy.
(7) Xが塩素原子である(1)～(5)のいずれかに記載の製造方法。 (7) The production method according to any one of (1) to (5), wherein X is a chlorine atom.
(8) 塩基がN-メチルイミダゾールである(1)～(7)のいずれかに記載の製造方法。 (8) The production method according to any one of (1) to (7), wherein the cocoon base is N-methylimidazole.
(9) 式(IV)： (9) Formula (IV):
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
(式中、R1はC1-6アルキルを表し、R3はC1-6アルキルを表す)で表される化合物又はその塩を還元剤で処理して、式(II)で表される化合物又はその塩を得る工程をさらに含む、(1)～(8)のいずれかに記載の製造方法。 (Wherein R 1 represents C 1-6 alkyl and R 3 represents C 1-6 alkyl) or a salt thereof is treated with a reducing agent and represented by formula (II) The production method according to any one of (1) to (8), further comprising a step of obtaining a compound or a salt thereof.
(10) R3がエチルである(9)記載の製造方法。 (10) The production method according to (9), wherein R 3 is ethyl.
(11) 還元剤が水素化アルミニウムリチウムである(9)又は(10)記載の製造方法。 (11) The production method according to (9) or (10), wherein the soot reducing agent is lithium aluminum hydride.
(12) 式(V)で表される化合物及び式(VI)： (12) Compound represented by Formula (V) and Formula (VI):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
(式中、R1及びR3はそれぞれ(9)又は(10)で定義した通りである)で表される化合物を反応させて、式(IV)で表される化合物又はその塩を得る工程をさらに含む、(9)～(11)のいずれかに記載の製造方法。 (Wherein R 1 and R 3 are as defined in (9) or (10), respectively) to obtain a compound represented by formula (IV) or a salt thereof The production method according to any one of (9) to (11), further comprising:
(13) 式(I)で表されるピロリジン化合物が、式(IA)： (13) A pyrrolidine compound represented by the formula (I) is represented by the formula (IA):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
で表されるピロリジン化合物である(1)～(12)のいずれかに記載の製造方法。 The production method according to any one of (1) to (12), which is a pyrrolidine compound represented by the formula:
　本発明により、ピロリジン化合物又はその塩の工業的な大量合成を志向した効率的な製造方法等が提供される。 The present invention provides an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.
　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.
　式(I)、(II)、(III)、(IV)、(V)及び(VI)の各基の定義において、 In the definition of each group of formula (I), (II), (III), (IV), (V) and (VI),
　C1-6アルキルとしては、例えば直鎖又は分岐状の炭素数1～6のアルキルがあげられ、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、sec-ペンチル、tert-ペンチル、ネオペンチル、ヘキシル等があげられ； C 1-6 alkyl includes, for example, linear or branched alkyl having 1 to 6 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl and the like;
　C12-24アルキルとしては、例えば直鎖又は分岐状の炭素数12～24のアルキルがあげられ、具体的にはドデシル、トリデシル、テトラデシル、2,6,10-トリメチルウンデシル、ペンタデシル、3,7,11-トリメチルドデシル、ヘキサデシル、ヘプタデシル、オクタデシル、6,10,14-トリメチルペンタデカン-2-イル、ノナデシル、2,6,10,14-テトラメチルペンタデシル、イコシル、3,7,11,15-テトラメチルヘキサデシル、ヘニコシル、ドコシル、トリコシル、テトラコシル等があげられ； Examples of the C 12-24 alkyl include linear or branched alkyl having 12 to 24 carbon atoms, specifically, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3, 7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15 -Tetramethylhexadecyl, henicosyl, docosyl, tricosyl, tetracosyl etc .;
　C12-24アルケニルとしては、例えば1～3つの二重結合を含む直鎖又は分岐状の炭素数12～24のアルケニルがあげられ、具体的には(Z)-トリデカ-8-エニル、(Z)-テトラデカ-9-エニル、(Z)-ペンタデカ-8-エニル、(Z)-ヘキサデカ-9-エニル、(Z)-ヘプタデカ-5-エニル、(Z)-オクタデカ-6-エニル、(Z)-ヘプタデカ-8-エニル、(Z)-オクタデカ-9-エニル、(E)-ヘプタデカ-8-エニル、(E)-オクタデカ-9-エニル、(Z)-ヘプタデカ-10-エニル、(Z)-オクタデカ-11-エニル、(8Z,11Z)-ヘプタデカ-8,11-ジエニル、(9Z,12Z)-オクタデカ-9,12-ジエニル、(8Z,11Z,14Z)-オクタデカ-8,11,14-トリエニル、(9Z,12Z,15Z)-オクタデカ-9,12,15-トリエニル、(Z)-ノナデカ-10-エニル、(Z)-イコサ-11-エニル、(10Z,13Z)-ノナデカ-10,13-ジエニル、(11Z,14Z)-イコサ-11,14-ジエニル、2,6,10-トリメチルウンデカ-1,5,9-トリエニル、3,7,11-トリメチルドデカ-2,6,10-トリエニル、2,6,10,14-テトラメチルペンタデカ-1-エニル、3,7,11,15-テトラメチルヘキサデカ-2-エニル等があげられる。 C 12-24 alkenyl includes, for example, linear or branched alkenyl having 12 to 24 carbon atoms containing 1 to 3 double bonds, specifically, (Z) -tridec-8-enyl, ( (Z) -tetradec-9-enyl, (Z) -pentadeca-8-enyl, (Z) -hexadeca-9-enyl, (Z) -heptadeca-5-enyl, (Z) -octadeca-6-enyl, ( (Z) -heptadeca-8-enyl, (Z) -octadeca-9-enyl, (E) -heptadeca-8-enyl, (E) -octadeca-9-enyl, (Z) -heptadeca-10-enyl, ( Z) -octadeca-11-enyl, (8Z, 11Z) -heptadeca-8,11-dienyl, (9Z, 12Z) -octadeca-9,12-dienyl, (8Z, 11Z, 14Z) -octadeca-8,11 , 14-trienyl, (9Z, 12Z, 15Z) -octadeca-9,12,15-trienyl, (Z) -nonadec-10-enyl, (Z) -icosa-11-enyl, (10Z, 13Z) -nonadeca -10,13-dienyl, (11Z, 14Z) -icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyl Examples include ludeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl and the like.
　本発明における式(IA)で表される化合物は、下記式(SS-IA)： The compound represented by the formula (IA) in the present invention is represented by the following formula (SS-IA):
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で表される(9Z,9'Z,12Z,12'Z)-((3S,4S)-1-メチルピロリジン-3,4-ジイル)ビス(メチレン) ビス(オクタデカ-9,12-ジエノアート)及び下記式(RR-IA)： (9Z, 9'Z, 12Z, 12'Z)-((3S, 4S) -1-methylpyrrolidine-3,4-diyl) bis (methylene) bis (octadeca-9,12-dienoate) And the following formula (RR-IA):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
で表される(9Z,9'Z,12Z,12'Z)-((3R,4R)-1-メチルピロリジン-3,4-ジイル)ビス(メチレン) ビス(オクタデカ-9,12-ジエノアート)の混合物である。なお、その混合比は1:1であり、ラセミ体である。 (9Z, 9'Z, 12Z, 12'Z)-((3R, 4R) -1-methylpyrrolidine-3,4-diyl) bis (methylene) bis (octadeca-9,12-dienoate) It is a mixture of The mixing ratio is 1: 1, which is a racemate.
　次に化合物(I)の製造方法について具体的に説明する。
製造方法1 Next, the production method of compound (I) will be specifically described.
Manufacturing method 1
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
(式中、R1、R2、R3及びXはそれぞれ前記と同義である)
工程1 (Wherein R 1 , R 2 , R 3 and X are as defined above)
Process 1
　化合物(IV)は、適当な溶媒中、化合物(V)及び化合物(VI)をホルムアルデヒド試薬及び必要により、モレキュラーシブズ4Aの存在下で反応させることにより得られる。 Compound (IV) can be obtained by reacting Compound (V) and Compound (VI) in the presence of a formaldehyde reagent and, if necessary, Molecular Sieves 4A in an appropriate solvent.
　化合物(VI)の使用量は特に限定されないが、化合物(V)に対し、例えば1.2～1.5当量である。 The amount of compound (VI) to be used is not particularly limited, but is, for example, 1.2 to 1.5 equivalents relative to compound (V).
　ホルムアルデヒド試薬としては特に限定されないが、例えばホルムアルデヒド、パラホルムアルデヒド等があげられ、好ましくはパラホルムアルデヒドである。ホルムアルデヒド試薬の使用量は特に限定されないが、化合物(V)に対し、例えば1.2～1.5当量である。ホルムアルデヒド試薬として、反応系中でホルムアルデヒドを発生させる試薬を用いてもよい。メタノールを酸化銅(II)又は白金により反応系中で酸化することで、ホルムアルデヒドが発生する(例えばBulletin de la Societe Chimique de France, 29, 1903,p.939-943、Angewandte Chemie, International Edition, 51(32), 2012, p.7985-7989等参照)。 The formaldehyde reagent is not particularly limited, and examples thereof include formaldehyde and paraformaldehyde, with paraformaldehyde being preferred. The amount of formaldehyde reagent used is not particularly limited, but is, for example, 1.2 to 1.5 equivalents relative to compound (V). As the formaldehyde reagent, a reagent that generates formaldehyde in the reaction system may be used. Oxidation of methanol with copper (II) oxide or platinum in the reaction system generates formaldehyde (e.g. Bulletin de la Societe Chimique de France, 29, 1903, p.939-943, Angelwandte Chemie, International Edition, 51 (32), 2012, p.7985-7989 etc.).
　モレキュラーシブズ4Aの使用量は特に限定されないが、化合物(V)に対し、例えば25～35wt%である。 The amount of molecular sieves 4A used is not particularly limited, but is, for example, 25 to 35 wt% with respect to compound (V).
　溶媒としては特に限定されないが、例えばテトラヒドロフラン(THF)等のエーテル溶媒；N,N-ジメチルアセトアミド等のアミド溶媒；ジクロロメタン等のハロゲン溶媒；トルエン、キシレン等の芳香族炭化水素；メタノール、エタノール等のアルコール溶媒等があげられ、これらを単独で、又は混合して用いられる。好ましい溶媒はトルエンである。溶媒の使用量は特に限定されないが、化合物(V)に対し、例えば2～50容量／重量(v/w)、好ましくは5～20v/wである。 Examples of the solvent include, but are not limited to, ether solvents such as tetrahydrofuran (THF); amide solvents such as N, N-dimethylacetamide; halogen solvents such as dichloromethane; aromatic hydrocarbons such as toluene and xylene; methanol, ethanol and the like. An alcohol solvent etc. are mention | raise | lifted and these are used individually or in mixture. A preferred solvent is toluene. The amount of the solvent to be used is not particularly limited, but it is, for example, 2 to 50 volume / weight (v / w), preferably 5 to 20 v / w, relative to compound (V).
　反応は、好ましくは70℃と110℃の間の温度で、より好ましくは90℃と100℃の間の温度で、通常5分間～72時間、好ましくは30分間～4時間行われる。 The reaction is preferably carried out at a temperature between 70 ° C. and 110 ° C., more preferably at a temperature between 90 ° C. and 100 ° C., usually for 5 minutes to 72 hours, preferably 30 minutes to 4 hours.
　化合物(V)は、市販品として、又は公知の方法(例えば、The Journal of Organic Chemistry, 44(7), 1979, p.1149-1154等)もしくはそれに準じた方法に従い得ることができる。 Compound (V) can be obtained as a commercially available product or according to a known method (for example, The Journal of Organic Chemistry, 44 (7), 1979, pp. 1149-1154, etc.) or a method analogous thereto.
　化合物(VI)は、市販品として、又は公知の方法(例えば、WO2001/092208等)もしくはそれに準じた方法に従い得ることができる。
工程2 Compound (VI) can be obtained as a commercially available product or according to a known method (for example, WO2001 / 092208 etc.) or a method analogous thereto.
Process 2
　化合物(II)は、適当な溶媒中、化合物(IV)を還元剤で処理することにより得られる。 Compound (II) can be obtained by treating compound (IV) with a reducing agent in an appropriate solvent.
　還元剤としては特に限定されないが、例えば水素化アルミニウムリチウム、水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム等があげられる。還元剤の使用量は特に限定されないが、化合物(IV)に対し、例えば1.1～15当量である。水素化アルミニウムリチウムは、反応性が高く化合物(IV)に対して小過剰な当量で反応を進行することができ、本反応における還元剤として好ましい。還元剤として水素化アルミニウムリチウムを用いる場合、化合物(IV)に対し、好ましくは1.1～1.5当量、より好ましくは1.2～1.4当量用いられる。 The reducing agent is not particularly limited, and examples thereof include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, lithium borohydride and the like. The amount of the reducing agent to be used is not particularly limited, but is, for example, 1.1 to 15 equivalents relative to compound (IV). Lithium aluminum hydride is preferable as a reducing agent in this reaction because it has high reactivity and can proceed with a small excess equivalent to the compound (IV). When lithium aluminum hydride is used as the reducing agent, it is preferably used in an amount of 1.1 to 1.5 equivalents, more preferably 1.2 to 1.4 equivalents, relative to compound (IV).
　溶媒としては特に限定されないが、例えばメタノール等のアルコール溶媒；THF等のエーテル溶媒；トルエン、キシレン等の芳香族炭化水素等があげられ、これらを単独で、又は混合して用いられる。好ましい溶媒はTHFである。溶媒の使用量は特に限定されないが、化合物(IV)に対して、例えば2～50容量／重量(v/w)、好ましくは10～20v/wである。 The solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol; ether solvents such as THF; aromatic hydrocarbons such as toluene and xylene, and these are used alone or in combination. A preferred solvent is THF. The amount of the solvent to be used is not particularly limited, but is, for example, 2 to 50 volume / weight (v / w), preferably 10 to 20 v / w, relative to compound (IV).
　反応は、好ましくは0℃と100℃の間の温度で、より好ましくは20℃と50℃の間の温度で、通常5分間～72時間、好ましくは30分間～4時間行われる。 The reaction is preferably performed at a temperature between 0 ° C. and 100 ° C., more preferably at a temperature between 20 ° C. and 50 ° C., usually for 5 minutes to 72 hours, preferably 30 minutes to 4 hours.
　還元剤として水素化アルミニウムリチウムを用いる場合、反応終了後に硫酸ナトリウム10水和物(Na2SO4・10H20)等の含水試薬で処理することにより、過剰量の水素化アルミニウムリチウムを不活性化することができ、析出した不溶物を濾別するだけで、純度良く化合物(II)を取得することができる。該化合物(II)は、他に精製操作を行うことなく、次工程に供することが可能である。工業的な大量合成を志向した場合、精製工程を少しでも省くことは非常に有用であり、本製造方法は優れた製造方法と言える。
工程3 When lithium aluminum hydride is used as the reducing agent, excess lithium aluminum hydride is inactivated by treatment with a water-containing reagent such as sodium sulfate decahydrate (Na 2 SO 4 · 10H 2 0) after the reaction is completed. The compound (II) can be obtained with high purity simply by filtering out the precipitated insoluble matter. The compound (II) can be subjected to the next step without any other purification operation. When industrial mass synthesis is aimed at, it is very useful to omit the purification step even a little, and this production method can be said to be an excellent production method.
Process 3
　化合物(I)は、化合物(II)及び化合物(III)を、塩基の存在下で反応させることにより得られる。 Compound (I) can be obtained by reacting Compound (II) and Compound (III) in the presence of a base.
（i）化合物(III)において、Xがヒドロキシの場合、化合物(I)は、適当な溶媒中、化合物(II)及び化合物(III)を、塩基及び添加剤の存在下で反応させることにより得られる。 (I) When X is hydroxy in compound (III), compound (I) is obtained by reacting compound (II) and compound (III) in the presence of a base and an additive in a suitable solvent. It is done.
　各試薬の使用量は特に限定されないが、化合物(II)に対し、化合物(III)は、例えば2.0～5.0当量、好ましくは2.0～2.2当量、塩基は、例えば4.0～8.0当量、好ましくは5.5～6.5当量、添加剤は、例えば1.6～2.6当量、好ましくは2.0～2.2当量である。 The amount of each reagent used is not particularly limited, but with respect to compound (II), compound (III) is, for example, 2.0 to 5.0 equivalents, preferably 2.0 to 2.2 equivalents, and the base is, for example, 4.0 to 8.0 equivalents, preferably 5.5 to 6.5 equivalents and additives are, for example, 1.6 to 2.6 equivalents, preferably 2.0 to 2.2 equivalents.
　溶媒としては特に限定されないが、例えばアセトニトリル等のニトリル溶媒；THF、2-メチルテトラヒドロフラン等のエーテル溶媒等があげられ、これらを単独で、又は混合して用いられる。好ましい溶媒はアセトニトリルである。溶媒の使用量は特に限定されないが、化合物(II)に対して、例えば2～100容量／重量(v/w)、好ましくは5～30v/wである。 The solvent is not particularly limited, and examples thereof include nitrile solvents such as acetonitrile; ether solvents such as THF and 2-methyltetrahydrofuran, and these are used alone or in combination. A preferred solvent is acetonitrile. The amount of the solvent to be used is not particularly limited, but is, for example, 2 to 100 volume / weight (v / w), preferably 5 to 30 v / w, relative to compound (II).
　塩基としては特に限定されないが、例えばN-メチルイミダゾール、トリエチルアミン、ピリジン、4-ジメチルアミノピリジン、炭酸水素ナトリウム等があげられ、好ましくはN-メチルイミダゾールである。 The base is not particularly limited, and examples thereof include N-methylimidazole, triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, and the like, and preferably N-methylimidazole.
　添加剤としては特に限定されないが、例えばパラトルエンスルホン酸クロリド、カルボニルジイミダゾール(CDI)等があげられ、好ましくはパラトルエンスルホン酸クロリドである。 The additive is not particularly limited, and examples thereof include p-toluenesulfonic acid chloride and carbonyldiimidazole (CDI), and p-toluenesulfonic acid chloride is preferable.
　反応は、好ましくは-10℃と80℃の間の温度で、より好ましくは0℃と10℃の間の温度で、通常5分間～72時間、好ましくは1時間～5時間行われる。 The reaction is preferably carried out at a temperature between −10 ° C. and 80 ° C., more preferably at a temperature between 0 ° C. and 10 ° C., usually for 5 minutes to 72 hours, preferably 1 hour to 5 hours.
　Xがヒドロキシである化合物(III)は、市販品として、又は公知の方法(例えば、Tetrahedron Letters, 49(22), 2008, p.3600-3603等)もしくはそれに準じた方法に従い得ることができる。 The compound (III) in which X is hydroxy can be obtained as a commercially available product or according to a known method (for example, Tetrahedron Letters, 49 (22), 2008, pp. 3600-3603) or a similar method.
（ii）化合物(III)において、Xが塩素原子の場合、化合物(I)は、適当な溶媒中、化合物(II)及び化合物(III)を、塩基の存在下で反応させることにより得られる。 (Ii) In the compound (III), when X is a chlorine atom, the compound (I) can be obtained by reacting the compound (II) and the compound (III) in the presence of a base in an appropriate solvent.
　各試薬の使用量は特に限定されないが、化合物(II)に対し、化合物(III)は、例えば1.6～2.6当量、好ましくは2.0～2.2当量、塩基は、例えば4.0～8.0当量、好ましくは4.5～5.5当量である。 The amount of each reagent used is not particularly limited, but with respect to compound (II), compound (III) is, for example, 1.6 to 2.6 equivalents, preferably 2.0 to 2.2 equivalents, and the base is, for example, 4.0 to 8.0 equivalents, preferably 4.5 to 5.5 equivalents.
　溶媒としては特に限定されないが、例えばTHF等のエーテル溶媒；アセトニトリル等のニトリル溶媒；酢酸エチル等のエステル溶媒等があげられ、これらを単独で、又は混合して用いられる。好ましい溶媒はアセトニトリルである。溶媒の使用量は特に限定されないが、化合物(II)に対して、例えば2～100容量／重量(v/w)、好ましくは10～30v/wである。 Examples of the solvent include, but are not limited to, ether solvents such as THF; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate and the like. These may be used alone or in combination. A preferred solvent is acetonitrile. The amount of the solvent to be used is not particularly limited, but is, for example, 2 to 100 volume / weight (v / w), preferably 10 to 30 v / w, relative to compound (II).
　塩基としては特に限定されないが、例えばジプロピルエチルアミン、N-メチルイミダゾール、トリエチルアミン、ピリジン、4-ジメチルアミノピリジン、炭酸水素ナトリウム等があげられ、好ましくはピリジンである。 The base is not particularly limited, and examples thereof include dipropylethylamine, N-methylimidazole, triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, and the like, and preferably pyridine.
　反応は、好ましくは0℃と80℃の間の温度で、より好ましくは20℃と50℃の間の温度で、通常5分間～72時間、好ましくは1時間～5時間行われる。 The reaction is preferably carried out at a temperature between 0 ° C. and 80 ° C., more preferably at a temperature between 20 ° C. and 50 ° C., usually for 5 minutes to 72 hours, preferably 1 hour to 5 hours.
　Xが塩素原子である化合物(III)は、市販品として、又は公知の方法(例えば、Bioorganic & Medicinal Chemistry Letters, 13(12), 2003, p.1977-1980等)もしくはそれに準じた方法に従い得ることができる。 The compound (III) in which X is a chlorine atom can be obtained as a commercially available product or according to a known method (for example, Bioorganic & Medicinal & Chemistry & Letters, 13 (12), 2003, p. 1977-1980, etc.) be able to.
上記各工程の生成物や中間体は、有機合成化学で常用される分離精製法、例えば、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して単離精製することができる。また、各工程の生成物や中間体は特に精製することなく次の反応に供することも可能である。 Products and intermediates in each of the above steps should be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can do. The products and intermediates in each step can be used for the next reaction without any particular purification.
　各工程で得られる中間体及び生成物の中には、幾何異性体、光学異性体等の立体異性体、互変異性体等が存在し得るものもあるが、本発明における中間体及び生成物は、これらを含め、全ての可能な異性体及びそれらの混合物を包含する。 Some intermediates and products obtained in each step may have stereoisomers such as geometric isomers and optical isomers, tautomers, etc., but the intermediates and products in the present invention Includes all possible isomers, including these, and mixtures thereof.
　また、各工程で用いられる原料化合物、得られる中間体及び生成物は、塩や溶媒和物の形態であってもよい。 In addition, the raw material compound used in each step, the obtained intermediate and product may be in the form of a salt or a solvate.
　各工程で得られる中間体及び生成物の塩を取得したいとき、各工程で得られる中間体及び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、各工程で得られる中間体及び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。 When it is desired to obtain the intermediate and product salt obtained in each step, the intermediate and product obtained in each step can be purified as they are, or obtained in a free form. In some cases, the intermediate and product obtained in each step are dissolved or suspended in a suitable solvent, and an acid or base is added to form a salt, which may be isolated and purified.
　各工程で用いられる原料化合物、得られる中間体及び生成物の塩は、例えば酸付加塩等を包含する。該酸付加塩としては、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等があげられる。 The starting compound used in each step, the resulting intermediate and the product salt include, for example, acid addition salts and the like. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, Examples thereof include organic acid salts such as benzoate and methanesulfonate.
　本発明の製造方法により、化合物(I)を公知の方法(例えばWO2011/136368)より短工程で簡便に得ることができる。また、医薬品の原料の合成方法は不純物の混入量を低減させることが重要であり、該製造方法は化合物(I)を一定の品質で効率的に再現性よく製造することができ、工業的製造方法として好適である。 According to the production method of the present invention, compound (I) can be easily obtained in a shorter process than known methods (for example, WO2011 / 136368). In addition, it is important that the method for synthesizing the raw materials for pharmaceuticals reduces the amount of impurities mixed in, and the production method can produce compound (I) efficiently with a certain quality with good reproducibility. It is suitable as a method.
　以下、本発明を実施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。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
　なお、実施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。 The proton nuclear magnetic resonance spectrum ( 1 H NMR) used in Examples is measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, what is usually used is used as the notation of the multiplicity of signals.
(9Z,9'Z,12Z,12'Z)-(1-メチルピロリジン-3,4-ジイル)ビス(メチレン) ビス(オクタデカ-9,12-ジエノアート) (化合物(IA))の製造
(工程1) Preparation of (9Z, 9'Z, 12Z, 12'Z)-(1-methylpyrrolidine-3,4-diyl) bis (methylene) bis (octadeca-9,12-dienoate) (compound (IA))
(Process 1)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　窒素雰囲気下、粉末状のモレキュラーシーブ4A(27.0 g)をトルエン(630 mL)に懸濁し、室温下、フマル酸ジエチル(90.0 g, 0.52 mol)、N-メチルグリシン(60.5 g, 0.68 mol)、パラホルムアルデヒド(23.5 g, 0.78 mol)及びトルエン(270 mL)を加えた後、90℃で2時間撹拌した。60℃まで冷却し、反応混合物に水(270 mL)を加え、室温まで冷却した。反応混合物を濾過し、トルエン(180 mL)で洗浄した。得られた濾液に水(180 mL)を加え、室温で10分間撹拌した後、10分間静置した。水層と有機層を分離した後、得られた有機層の溶媒を減圧留去し、trans-formであるジエチル　1-メチルピロリジン-3,4-ジカルボキシラート(化合物MP)(116 g, 収率97.2%)を得た。 Under nitrogen atmosphere, powdered molecular sieve 4A (27.0 g) is suspended in toluene (630 ml), and at room temperature, diethyl fumarate (90.0 g, 0.52 mol), N-methylglycine (60.5 g, 0.68 mol), Paraformaldehyde (23.5 g, 0.78 mol) and toluene (270 mL) were added, followed by stirring at 90 ° C for 2 hours. The reaction mixture was cooled to 60 ° C., water (270 mL) was added, and the mixture was cooled to room temperature. The reaction mixture was filtered and washed with toluene (180 mL). Water (180 mL) was added to the obtained filtrate, stirred for 10 minutes at room temperature, and then allowed to stand for 10 minutes. After separating the aqueous layer and the organic layer, the solvent of the obtained organic layer was distilled off under reduced pressure, and diethyl 1-methylpyrrolidine-3,4-dicarboxylate (compound MP) (116 kg, collected as a trans-form) was collected. 97.2%).
1H NMR (300 MHz, CDCl3) δ: 1.27 (t, J = 7.2 Hz, 6H), 2.33 (s, 3H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 2H), 3.40-3.49 (m, 2H), 4.17 (q, J = 7.2 Hz, 4H).
(工程2) 1 H NMR (300 MHz, CDCl 3 ) δ: 1.27 (t, J = 7.2 Hz, 6H), 2.33 (s, 3H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 2H), 3.40 -3.49 (m, 2H), 4.17 (q, J = 7.2 Hz, 4H).
(Process 2)
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
窒素雰囲気下、THF(114 mL)を5℃に冷却し、水素化アルミニウムリチウム(1 mol/L THF溶液, 53.7 mL, 53.7 mmol)を加えた。反応混合物に、工程1で得られた化合物MP(9.46 g, 41.3 mmol)をTHF(28.4 mL)で溶解した溶液を、内温を0-15℃に保ちながら滴下し室温で2時間撹拌した。反応混合物に硫酸ナトリウム10水和物(39.9 g, 124 mmol)をゆっくり加え、35℃で1時間撹拌した。反応混合物を、室温まで冷却した後、濾過し、残渣をTHF(56.8 mL)で洗浄した。得られた濾液をエバポレーターで液量が60 mL程度になるまで濃縮した。得られた溶液に、アセトニトリル(142 mL)を加えて、エバポレーターで液量が60 mL程度になるまで濃縮した。該アセトリニトルへの溶媒置換操作を、更に、2回行うことにより、trans-formである(1-メチルピロリジン-3,4-ジイル)ジメタノール(化合物MPM)のアセトニトリル溶液(56.8 mL)を得た。
(工程3) Under a nitrogen atmosphere, THF (114 mL) was cooled to 5 ° C., and lithium aluminum hydride (1 mol / L THF solution, 53.7 mL, 53.7 mmol) was added. A solution prepared by dissolving the compound MP (9.46 g, 41.3 mmol) obtained in Step 1 with THF (28.4 mL) was added dropwise to the reaction mixture while maintaining the internal temperature at 0-15 ° C., and the mixture was stirred at room temperature for 2 hours. Sodium sulfate decahydrate (39.9 g, 124 mmol) was slowly added to the reaction mixture, and the mixture was stirred at 35 ° C. for 1 hr. The reaction mixture was cooled to room temperature and then filtered, and the residue was washed with THF (56.8 mL). The obtained filtrate was concentrated with an evaporator until the liquid volume reached about 60 mL. Acetonitrile (142 mL) was added to the resulting solution, and the mixture was concentrated with an evaporator until the liquid volume reached about 60 mL. The solvent substitution operation to the acetrinitol was further performed twice to obtain an acetonitrile solution (56.8 mL) of trans-form (1-methylpyrrolidine-3,4-diyl) dimethanol (compound MPM). .
(Process 3)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　窒素雰囲気下、(9Z,12Z)-オクタデカ-9,12-ジエン酸(23.1 g, 82.5 mmol)をアセトニトリル(56.8 mL)に溶解し、N-メチルイミダゾール(20.3 g, 248 mmol)を加え、5℃に冷却した。反応混合物に、p-トルエンスルホニルクロリド(16.5 g, 86.6 mmol)のアセトニトリル(56.8 mL)溶液を滴下し、5℃で1時間撹拌した。反応混合物に、工程2で得られた化合物MPMのアセトニトリル溶液(56.8 mL)を滴下し、アセトニトリル(18.9 mL)を加え、5℃で3時間撹拌した。反応混合物に、水(56.8 mL)及びn-ヘプタン(56.8 mL)を加え、室温で10分間撹拌した後、10分間静置した。水層と有機層を分離した後、得られた有機層に水(28.4 mL)及びアセトニトリル(56.8 mL)を加え、室温で10分間撹拌した後、10分間静置した。水層と有機層を分離した後、得られた有機層に水(14.2 mL)及びアセトニトリル(28.4 mL)を加え、室温で10分間撹拌した後、10分間静置した。水層と有機層を分離し、得られた有機層にNHシリカゲル(45 g, 富士シリシア社製NH-DM1020)を加え、室温で0.5時間撹拌した。混合物を濾過し、NHシリカゲルを酢酸エチル(189 mL)で洗浄した。得られた濾液の溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー(n-ヘプタン:酢酸エチル=30:1→0:1)精製した。次に、NHシリカゲルを用いて、シリカゲルクロマトグラフィー(n-ヘプタン:酢酸エチル=10:1)精製をすることにより、化合物(IA) (17.0 g, 2工程トータル収率62%)を得た 。 Under a nitrogen atmosphere, (9Z, 12Z) -octadeca-9,12-dienoic acid (23.1 g, 82.5 mmol) was dissolved in acetonitrile (56.8 mL), N-methylimidazole (20.3 g, 248 mmol) was added, and 5 Cooled to ° C. A solution of p-toluenesulfonyl chloride (16.5 g, 86.6 mmol) in acetonitrile (56.8 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 5 ° C. for 1 hour. To the reaction mixture, an acetonitrile solution (56.8 mL) of the compound MPM obtained in Step 2 was added dropwise, acetonitrile (18.9 mL) was added, and the mixture was stirred at 5 ° C. for 3 hours. Water (56.8 mL) and n-heptane (56.8 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and then allowed to stand for 10 minutes. After separating the aqueous layer and the organic layer, water (28.4 mL) and acetonitrile (56.8 mL) were added to the obtained organic layer, and the mixture was stirred at room temperature for 10 minutes and then allowed to stand for 10 minutes. After separating the aqueous layer and the organic layer, water (14.2 mL) and acetonitrile (28.4 mL) were added to the obtained organic layer, and the mixture was stirred at room temperature for 10 minutes and then allowed to stand for 10 minutes. The aqueous layer and the organic layer were separated, and NH silica gel (45 g, NH-DM1020 manufactured by Fuji Silysia) was added to the obtained organic layer, followed by stirring at room temperature for 0.5 hour. The mixture was filtered and the NH silica gel was washed with ethyl acetate (189 mL). The solvent of the obtained filtrate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (n-heptane: ethyl acetate = 30: 1 → 0: 1). Next, purification by silica gel chromatography (n-heptane: ethyl acetate = 10: 1) using NH silica gel gave Compound (IA) (17.0 g, total yield of 2 steps, 62%).   .
ESI-MS m/z: 671 (M+H)+; 1H NMR (300 MHz, CDCl3) δ: 0.89 (t, J = 6.8 Hz, 6H), 1.22-1.42 (m, 28H), 1.55-1.68 (m, 4H), 2.05 (q, J = 6.8 Hz, 8H), 2.14-2.26 (m, 2H), 2.27-2.39 (m, 9H), 2.67 (dd, J = 9.2, 7.2 Hz, 2H), 2.77 (t, J = 5.9 Hz, 4H), 3.97-4.14 (m, 4H), 5.26-5.46 (m, 8H). ESI-MS m / z: 671 (M + H) + ; 1 H NMR (300 MHz, CDCl 3 ) δ: 0.89 (t, J = 6.8 Hz, 6H), 1.22-1.42 (m, 28H), 1.55- 1.68 (m, 4H), 2.05 (q, J = 6.8 Hz, 8H), 2.14-2.26 (m, 2H), 2.27-2.39 (m, 9H), 2.67 (dd, J = 9.2, 7.2 Hz, 2H) , 2.77 (t, J = 5.9 Hz, 4H), 3.97-4.14 (m, 4H), 5.26-5.46 (m, 8H).
(9Z,9'Z,12Z,12'Z)-(1-メチルピロリジン-3,4-ジイル)ビス(メチレン) ビス(オクタデカ-9,12-ジエノアート) (化合物(IA))の製造 Preparation of (9Z, 9'Z, 12Z, 12'Z)-(1-methylpyrrolidine-3,4-diyl) bis (methylene) bis (octadeca-9,12-dienoate) (compound (IA))
窒素雰囲気下、実施例1の工程2に準じて得られる化合物MPM(12.0 g, 82.6 mmol)、ピリジン(33.4 mL, 413 mmol)及び(9Z,12Z)-オクタデカ-9,12-ジエン酸クロリド(55.8 mL, 174 mmol)を加え、室温で5時間撹拌した。反応混合物に水(120 mL)及びn-ヘプタン(120 mL)を加え、室温で10分間撹拌した後、10分間静置した。水層と有機層を分離した後、得られた有機層の溶媒を減圧留去した。得られた残渣を、NHシリカゲルを用いて、シリカゲルクロマトグラフィー(n-ヘキサン：酢酸エチル=100：1→3：7)精製した。得られた生成物にn-ヘプタン(290 mL)及び活性炭(870 mg)を加え、40℃で0.5時間撹拌した後、混合物を濾過し、n-ヘプタン(100 mL)で洗浄した。得られた濾液の溶媒を減圧留去し、化合物(IA)(27.8 g, 収率52.8%)を得た。 Under a nitrogen atmosphere, the compounds MPM (12.0 g, 82.6 mmol), pyridine (33.4 mL, 413 mmol) and (9Z, 12Z) -octadeca-9,12-dienoic acid chloride obtained according to Step 2 of Example 1 ( 55.8 mL, 174 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water (120 mL) and n-heptane (120 mL) were added to the reaction mixture, stirred at room temperature for 10 minutes, and then allowed to stand for 10 minutes. After separating the aqueous layer and the organic layer, the solvent of the obtained organic layer was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 100: 1 → 3: 7) using NH silica gel. N-Heptane (290 mL) and activated carbon (870 mL) were added to the obtained product, and the mixture was stirred at 40 ° C. for 0.5 hour, and then the mixture was filtered and washed with n-heptane (100 mL). The solvent of the obtained filtrate was distilled off under reduced pressure to obtain Compound (IA) (27.8 g, yield 52.8%).
本発明により、ピロリジン化合物又はその塩の工業的な大量合成を志向した効率的な製造方法等が提供される。 The present invention provides an efficient production method and the like aimed at industrial mass synthesis of pyrrolidine compounds or salts thereof.

Claims (13)

  1. 　式(II)で表される化合物又はその塩を、塩基の存在下、式(III)で表される化合物と反応させる、式(I)：
    Figure JPOXMLDOC01-appb-C000001
     (式中、R1はC1-6アルキルを表し、R2はC12-24アルキル又はC12-24アルケニルを表し、Xはヒドロキシ又は塩素原子を表す)で表されるピロリジン化合物又はその塩の製造方法。     A compound represented by the formula (II) or a salt thereof is reacted with a compound represented by the formula (III) in the presence of a base, the formula (I):
    Figure JPOXMLDOC01-appb-C000001
     (Wherein R 1 represents C 1-6 alkyl, R 2 represents C 12-24 alkyl or C 12-24 alkenyl, and X represents a hydroxy or chlorine atom) or a salt thereof Manufacturing method.
  2. 　R1がメチルである請求項1に記載の製造方法。 2. The production method according to claim 1, wherein R 1 is methyl.
  3. 　R2がC12-24アルケニルである請求項1又は2に記載の製造方法。 3. The production method according to claim 1, wherein R 2 is C 12-24 alkenyl.
  4. 　R2がヘプタデカジエニルである請求項1又は2に記載の製造方法。 3. The production method according to claim 1, wherein R 2 is heptadecadienyl.
  5. 　R2が(8Z,11Z)-ヘプタデカ-8,11-ジエニルである請求項1又は2に記載の製造方法。 3. The production method according to claim 1, wherein R 2 is (8Z, 11Z) -heptadeca-8,11-dienyl.
  6. 　Xがヒドロキシである請求項1～5のいずれか1項に記載の製造方法。 The production method according to any one of claims 1 to 5, wherein X is hydroxy.
  7. 　Xが塩素原子である請求項1～5のいずれか1項に記載の製造方法。 The production method according to any one of claims 1 to 5, wherein X is a chlorine atom.
  8. 　塩基がN-メチルイミダゾールである請求項1～7のいずれか1項に記載の製造方法。 The production method according to any one of claims 1 to 7, wherein the base is N-methylimidazole.
  9. 　式(IV)：
    Figure JPOXMLDOC01-appb-C000002
     (式中、R1はC1-6アルキルを表し、R3はC1-6アルキルを表す)で表される化合物又はその塩を還元剤で処理して、式(II)で表される化合物又はその塩を得る工程をさらに含む、請求項1～8のいずれか1項に記載の製造方法。     Formula (IV):
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 1 represents C 1-6 alkyl and R 3 represents C 1-6 alkyl) or a salt thereof is treated with a reducing agent and represented by formula (II) The production method according to any one of claims 1 to 8, further comprising a step of obtaining a compound or a salt thereof.
  10. 　R3がエチルである請求項9記載の製造方法。 10. The production method according to claim 9, wherein R 3 is ethyl.
  11. 　還元剤が水素化アルミニウムリチウムである請求項9又は10記載の製造方法。 The production method according to claim 9 or 10, wherein the reducing agent is lithium aluminum hydride.
  12. 　式(V)で表される化合物及び式(VI)：
    Figure JPOXMLDOC01-appb-C000003
     (式中、R1及びR3はそれぞれ請求項9又は10で定義した通りである)で表される化合物を反応させて、式(IV)で表される化合物又はその塩を得る工程をさらに含む、請求項9～11のいずれか1項に記載の製造方法。     Compound represented by formula (V) and formula (VI):
    Figure JPOXMLDOC01-appb-C000003
     (Wherein R 1 and R 3 are as defined in claim 9 or 10, respectively), and a step of obtaining a compound represented by the formula (IV) or a salt thereof The production method according to any one of claims 9 to 11, further comprising:
  13. 　式(I)で表されるピロリジン化合物が、式(IA)：
    Figure JPOXMLDOC01-appb-C000004
     で表されるピロリジン化合物である請求項1～12のいずれか1項に記載の製造方法。     The pyrrolidine 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 12, which is a pyrrolidine compound represented by the formula:
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