WO2009104557A1 - Process for production of n-(3-pyrrolidinyl)glycine derivative - Google Patents

Process for production of n-(3-pyrrolidinyl)glycine derivative Download PDF

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WO2009104557A1
WO2009104557A1 PCT/JP2009/052549 JP2009052549W WO2009104557A1 WO 2009104557 A1 WO2009104557 A1 WO 2009104557A1 JP 2009052549 W JP2009052549 W JP 2009052549W WO 2009104557 A1 WO2009104557 A1 WO 2009104557A1
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pyrrolidinyl
group
benzyl
glycine derivative
carbon atoms
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French (fr)
Japanese (ja)
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進 天野
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株式会社カネカ
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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
    • C07D207/10—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 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a method for producing an N- (3-pyrrolidinyl) glycine derivative and an important intermediate thereof.
  • N- (3-pyrrolidinyl) glycine derivatives are important intermediates in the production of pharmaceuticals, agricultural chemicals, chemical products and the like.
  • Patent Document 1 As a method for producing the N- (3-pyrrolidinyl) glycine derivative represented by the formula (1), a method using 3-amino-1- (tert-butoxycarbonyl) pyrrolidine is known (Patent Document 1).
  • the present invention aims to efficiently produce an N- (3-pyrrolidinyl) glycine derivative that is important in the production of pharmaceuticals and the like using a general-purpose and readily available compound as a raw material. is there.
  • the present invention has the general formula (3):
  • R 1 represents a hydrogen atom or a benzyl group.
  • R 2 represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, Represents an optionally substituted aralkyl group having 7 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal, and * represents an asymmetric carbon atom.
  • the present invention also has the general formula (4):
  • the target compound can be easily obtained.
  • an N- (1-benzyl-3-pyrrolidinyl) glycine derivative or a salt thereof is obtained from a general-purpose and readily available 1-benzyl-3-aminopyrrolidine derivative or a salt thereof, various fields including the pharmaceutical field
  • an N- (3-pyrrolidinyl) glycine derivative that is important in production can be produced particularly easily.
  • handling is also easy, it is advantageous on industrial production.
  • the production method of the present invention basically comprises (a) a 1-benzyl-3-aminopyrrolidine derivative represented by the general formula (1) according to the following reaction formula. Converting to 1-benzyl-3-pyrrolidinyl) glycine derivative; (B) a step of converting this into an N- (3-pyrrolidinyl) glycine derivative represented by the general formula (4).
  • step (b) it is not always necessary to use the compound obtained by the method of the step (a), and those obtained by other methods may be used, and each step is performed independently. Also good.
  • Step (a) In this step (a), the 1-benzyl-3-aminopyrrolidine derivative represented by the formula (1) or a salt thereof (hereinafter also referred to as the compound (1)) is added to the general formula (2):
  • R 1 represents a hydrogen atom or a benzyl group. Preferably it is a hydrogen atom.
  • Such compounds are generally readily available and are suitable for use as raw materials. When such a compound is used, the target compound can be synthesized only by hydrogenation without protection or deprotection, as described later.
  • R 2 represents an alkyl group which may be substituted having 1 to 20 carbon atoms, an alkenyl group which may be substituted having 2 to 20 carbon atoms, or 7 to 7 carbon atoms.
  • 20 represents an optionally substituted aralkyl group, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal.
  • methyl group, ethyl group, isopropyl group, tert-butyl group, hydrogen atom, sodium or potassium Particularly preferred is a methyl group or an ethyl group.
  • * represents an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom may be either (R) or (S), and one of both enantiomers that is slightly excessive is also included in the present invention.
  • the above general formulas (1) and (3) can also be used in the form of a salt with an acid.
  • the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these.
  • X represents a leaving group.
  • the leaving group is not particularly limited, and examples thereof include a halogen atom, a sulfonyloxy group, and a phosphoryloxy group.
  • the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • the sulfonyloxy group is a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, m-nitrobenzene.
  • it is a halogen atom, More preferably, it is a chlorine atom or a bromine atom.
  • the amount of compound (2) to be used is not particularly limited, but is usually 0.5 to 3.0-fold mol amount, preferably 0.8 to 2.0-fold mol amount based on compound (1). More preferably, the molar amount is 1.0 to 1.5 times.
  • a base may be added as necessary.
  • the base used is not particularly limited, and examples thereof include metal amides such as lithium amide, sodium amide, lithium diisopropylamide, and magnesium chloride diisopropylamide; organolithium reagents such as methyllithium and n-butyllithium; methylmagnesium bromide, Grignard reagents such as tert-butylmagnesium chloride; metal alkoxides such as sodium methoxide, magnesium ethoxide and potassium tert-butoxide; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; Lithium, sodium carbonate, potassium carbonate, sodium carbonate, calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, etc .; lithium hydroxide, hydroxide Metal hydroxides such as thorium and potassium hydroxide; metal acetates such as lithium acetate, sodium
  • the amount of the base used is not particularly limited, but is usually 0.5 to 4.0 times the molar amount relative to the compound (1), preferably 0.8 to 3.0 times the molar amount, and more preferably Is 1.0 to 2.0 times the molar amount.
  • a reaction solvent is not particularly required, but depending on the reaction substrate, a reaction solvent may be used.
  • the reaction solvent used for the reaction is water, an organic solvent, or a mixed solvent of water and an organic solvent.
  • the organic solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol, ethanol, n-butanol, isopropanol, ethylene glycol, and methoxy alcohol; hydrocarbon solvents such as benzene, toluene, n-hexane, and cyclohexane; diethyl ether , Tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether, and other ether solvents; ethyl acetate, butyl acetate, and other ester solvents; acetone, methyl ethyl ketone, and other ketone solvents; methylene chloride, chloroform Halogen-based solvents such as 1,1,1-trichloroethane; nitrogen-containing solvents such as acetonitrile, acetamide, dimethylformamide, dimethylacetamide, N-methylpyr
  • the reaction temperature in this step is not particularly limited, but is preferably ⁇ 30 ° C. to 160 ° C., more preferably ⁇ 20 ° C. to 50 ° C. Particularly preferred is 0 to 30 ° C.
  • the reaction procedure is not particularly limited, and all the reagents may be added at once. However, a base is added to the solution of compound (1), and then compound (2) is added.
  • the obtained reaction solution may be used for the next step as it is, but in order to obtain a product from the reaction solution, general post-treatment may be performed.
  • general post-treatment For example, after completion of the reaction, the pH of the reaction solution is adjusted as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like.
  • reaction solvent may be distilled off by an operation such as heating under reduced pressure, and then the same operation may be performed, or after adding water as necessary, the reaction solvent may be distilled off.
  • the pH of the reaction solution may be adjusted at a predetermined temperature and the precipitated crystals may be filtered.
  • the target product thus obtained is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography, etc.
  • the obtained object may be dried using a dryer or the like.
  • the solvent used for the crystallization is not particularly limited.
  • N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the formula (3) obtained in this step or a salt thereof is a novel compound not described in any literature.
  • Step (b) the N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the above formula (3) or a salt thereof (hereinafter also referred to as compound (3)) is debenzylated.
  • an N- (3-pyrrolidinyl) glycine derivative represented by the above formula (4) or a salt thereof is prepared.
  • * represents an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom may be either (R) or (S), and one of both enantiomers that is slightly excessive is also included in the present invention.
  • the above general formulas (3) and (4) can also be used in the form of a salt with an acid.
  • the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these.
  • the method for debenzylation is not particularly limited, but preferably a method of hydrolysis with hydrochloric acid, sulfuric acid, etc., a method of hydrolysis after reacting with allyl chlorocarbonate, ethyl chlorocarbonate, etc., in the presence of a transition metal catalyst.
  • This is a method of hydrogenation. More preferred is a method of hydrogenation in the presence of a transition metal catalyst.
  • transition metal catalyst used in the above method examples include metals such as platinum, rhodium, palladium, nickel, ruthenium, iridium, rhenium, alloys, and chlorides thereof.
  • a catalyst dispersed in a powder carrier from the viewpoints of catalyst activity, reproducibility, storage stability, operability, and recycling.
  • the powder carrier examples include carbon, alumina, silica-alumina, silica, barium carbonate, barium sulfate, calcium carbonate, titanium oxide, zirconium oxide, and zeolite, and preferably platinum supported on these powder carriers. , Rhodium, or palladium metal, sulfide thereof, or hydroxide.
  • transition metal catalysts may be used alone or in combination of two or more.
  • Preferred is palladium-carbon, rhodium-carbon, platinum-carbon or palladium hydroxide (II) -carbon, more preferred is palladium-carbon or palladium (II) -carbon, and particularly preferred is water.
  • Palladium (II) oxide-carbon is particularly preferred.
  • the amount of the transition metal catalyst used is too large, it is not preferable from the viewpoint of cost and post-treatment, and therefore it is preferably 5 times or less by weight with respect to the compound (3), more preferably 0.01 to 0.00. 5 times the weight.
  • reaction solvent used for the reaction is water, an organic solvent, or a mixed solvent of water and an organic solvent.
  • the organic solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol, ethanol, n-butanol, isopropanol, ethylene glycol, and methoxy alcohol; hydrocarbon solvents such as benzene, toluene, n-hexane, and cyclohexane; diethyl Ether solvents such as ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; methylene chloride, Halogen-based solvents such as chloroform and 1,1,1-trichloroethane; nitrogen-containing systems such as acetonitrile, acetamide, dimethylformamide, dimethylacetamide, and N-methylpyrrol
  • the hydrogen pressure in this step is preferably 50 bar or less, more preferably 1 to 10 bar.
  • the reaction temperature in this step is not particularly limited, but is preferably ⁇ 30 ° C. to 160 ° C., more preferably 0 ° C. to 50 ° C. Particularly preferred is 0 to 30 ° C.
  • This reaction may be carried out by further adding an acid for the purpose of improving the reaction rate.
  • the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these. An inorganic acid is preferable, and hydrogen chloride or sulfuric acid is more preferable.
  • the reaction procedure is not particularly limited, and it is only necessary to add all reagents at once. Usually, an acid is added to the solution of the compound (3) as necessary, and then a transition metal catalyst is added. It is only necessary to add hydrogen gas.
  • the target product can be obtained by filtering the catalyst from the reaction solution after completion of the reaction and distilling the reaction solvent from the filtrate by operation such as heating under reduced pressure.
  • the target product thus obtained is almost pure, but the purity may be further increased by adding purification by general techniques such as crystallization purification, fractional distillation, column chromatography and the like.
  • the obtained object may be dried using a dryer or the like.
  • the solvent used for the crystallization is not particularly limited because it varies depending on the compound.
  • N- (3-pyrrolidinyl) glycine derivative represented by the formula (4) obtained in this step or a salt thereof is a novel compound not described in any literature.
  • N- (3-pyrrolidinyl) glycine derivatives are prepared by protecting the amino group of the N- (3-pyrrolidinyl) glycine derivative, or a salt thereof, produced by the above method, if necessary. be able to.
  • protecting group and the protecting method examples include protecting groups and protecting methods described in PROTECTIVEECTGROUPS in ORGANIC SYNTHESIS pp.503-659.
  • the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 2.1 g (73% yield) of N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester.
  • Example 4 N-((R) -3-pyrrolidinyl) glycine ethyl ester N-benzyl-N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester 88 mg (0.25 mmol) was added to 2 ml of ethanol. Concentrated hydrochloric acid 74 mg (0.75 mmol) and 5% Pd—C (containing 50% water) 34 mg were added to the solution dissolved in. Hydrogen substitution was performed and the mixture was stirred at room temperature for 17 hours. Pd—C was filtered off from the reaction solution and washed with 5 ml of ethanol. The filtrate was concentrated under reduced pressure to obtain 50 mg (yield 92%) of N-((R) -3-pyrrolidinyl) glycine ethyl ester.

Abstract

Disclosed is a process for producing an N-(3-pyrrolidinyl)glycine derivative by debenzylating an N-(1-benzyl-3-pyrrolidinyl)glycine derivative. It is particularly preferred to produce an N-(1-benzyl-3-pyrrolidinyl)glycine derivative by using an 1-benzyl-3-aminopyrrolidine derivative (a substance that is readily available on an industrial scale) as a starting substance, and to produce the N-(3-pyrrolidinyl)glycine derivative by using the N-(1-benzyl-3-pyrrolidinyl)glycine derivative. The process enables the production of an N-(3-pyrrolidinyl)glycine derivative which is useful as an intermediate for a pharmaceutical agent with high efficiency by using a readily available, general-purpose compound.

Description

Ｎ－（３－ピロリジニル）グリシン誘導体の製造法Process for producing N- (3-pyrrolidinyl) glycine derivative
　本発明は、Ｎ－（３－ピロリジニル）グリシン誘導体の製造法、及びその重要中間体に関する。Ｎ－（３－ピロリジニル）グリシン誘導体は医薬品、農薬、化成品等の製造上重要な中間体である。 The present invention relates to a method for producing an N- (3-pyrrolidinyl) glycine derivative and an important intermediate thereof. N- (3-pyrrolidinyl) glycine derivatives are important intermediates in the production of pharmaceuticals, agricultural chemicals, chemical products and the like.
　一般式（４）： General formula (4):
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
で表されるＮ－（３－ピロリジニル）グリシン誘導体の製造法に関しては従来、３－アミノ－１－（ｔｅｒｔ－ブトキシカルボニル）ピロリジンを用いる方法（特許文献１）が知られている。 As a method for producing the N- (3-pyrrolidinyl) glycine derivative represented by the formula (1), a method using 3-amino-1- (tert-butoxycarbonyl) pyrrolidine is known (Patent Document 1).
　この製法の出発物質である、３－アミノ－１－（ｔｅｒｔ－ブトキシカルボニル）ピロリジンの一般的な製造法としては、
ｉ）３－ヒドロキシピロリジンを用い、水酸基をメシル化し、アジドで置換した後、接触還元する方法（特許文献２）、
ii）アスパラギン酸を用い、アミノ基を保護し、環化反応後、還元する方法（特許文献３）、
iii）４－ヒドロキシプロリンを脱炭酸した後、水酸基をメシル化し、アジドで置換した後、接触還元する方法（特許文献４）、
等が知られている。
ＷＯ０３／０４５９４２ 特開平１０－２０４０８６ 特開２００１－１１４７５９ 特開２００２－２１２１５５ As a general production method of 3-amino-1- (tert-butoxycarbonyl) pyrrolidine which is a starting material of this production method,
i) a method in which 3-hydroxypyrrolidine is used to mesylate a hydroxyl group and replace with azide, followed by catalytic reduction (Patent Document 2),
ii) A method in which aspartic acid is used to protect the amino group, and the cyclization reaction is followed by reduction (Patent Document 3).
iii) A method in which 4-hydroxyproline is decarboxylated, the hydroxyl group is mesylated, substituted with azide, and then catalytically reduced (Patent Document 4)
Etc. are known.
WO03 / 045942 JP-A-10-204086 JP 2001-114759 A JP 2002-212155 A
　しかしｉ）、iii）の方法では、爆発性があり、取り扱いが困難なアジド化剤を使用する必要がある。また、ii）の方法では、多数の保護、脱保護工程が必要となる。従って、３－アミノ－１－（ｔｅｒｔ－ブトキシカルボニル）ピロリジンは製造が容易ではなく、一般的に高価であり、入手先が限定される。 However, in the methods i) and iii), it is necessary to use an azidating agent that is explosive and difficult to handle. In the method ii), many protection and deprotection steps are required. Therefore, 3-amino-1- (tert-butoxycarbonyl) pyrrolidine is not easy to produce, is generally expensive, and its source is limited.
　特許文献１の方法では、この３－アミノ－１－（ｔｅｒｔ－ブトキシカルボニル）ピロリジンを出発物質として使用する必要がある為、工業的な利用に問題がある。 In the method of Patent Document 1, since it is necessary to use 3-amino-1- (tert-butoxycarbonyl) pyrrolidine as a starting material, there is a problem in industrial use.
　本発明は、上記現状に鑑み、汎用的で、入手容易な化合物を原料として、医薬品等の製造上重要なＮ－（３－ピロリジニル）グリシン誘導体を効率的に製造することを目的とするものである。 In view of the above situation, the present invention aims to efficiently produce an N- (3-pyrrolidinyl) glycine derivative that is important in the production of pharmaceuticals and the like using a general-purpose and readily available compound as a raw material. is there.
　すなわち本発明は、一般式（３）： That is, the present invention has the general formula (3):
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ１は水素原子、又はベンジル基を表す。Ｒ２は、炭素数１～２０の置換されていても良いアルキル基、炭素数２～２０の置換されていても良いアルケニル基、炭素数７～２０の置換されていても良いアラルキル基、炭素数６～２０の置換されていても良いアリール基、水素原子、又はアルカリ金属を表す。＊は不斉炭素原子であることを表す。）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩の製造方法であって、
一般式（１）： (Wherein R 1 represents a hydrogen atom or a benzyl group. R 2 represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, Represents an optionally substituted aralkyl group having 7 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal, and * represents an asymmetric carbon atom. A method for producing an N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the formula:
General formula (1):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ１、＊は前記と同じ。）で表される１－ベンジル－３－アミノピロリジン誘導体、又はその塩に、一般式（２）： (Wherein R 1 and * are the same as defined above), a 1-benzyl-3-aminopyrrolidine derivative represented by the formula:
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ２は前記と同じ。Ｘは脱離基を表す。）で表される化合物を反応させることを特徴とする方法である。 (Wherein R 2 is the same as described above, X represents a leaving group).
　本発明は、また、一般式（４）： The present invention also has the general formula (4):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ２、＊は前記に同じ。）で表されるＮ－（３－ピロリジニル）グリシン誘導体、又はその塩の製造方法であって、
前記式（３）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩を、脱ベンジル化することを特徴とする方法でもある。 (Wherein R 2 and * are as defined above), a method for producing an N- (3-pyrrolidinyl) glycine derivative, or a salt thereof,
In this method, the N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the formula (3) or a salt thereof is debenzylated.
　Ｎ－（１－ベンジル－３－ピロリジニル）グリシン誘導体又はその塩からＮ－（３－ピロリジニル）グリシン誘導体を得る本発明にかかる方法によれば、簡便に目的化合物を得ることができる。特に、汎用的で、入手容易な１－ベンジル－３－アミノピロリジン誘導体又はその塩からＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体又はその塩を得た場合、医薬分野をはじめ、多方面において製造上重要なＮ－（３－ピロリジニル）グリシン誘導体を特に簡便に製造することができる。また、取扱いも容易であるため、工業生産上有利である。 According to the method of the present invention for obtaining an N- (3-pyrrolidinyl) glycine derivative from an N- (1-benzyl-3-pyrrolidinyl) glycine derivative or a salt thereof, the target compound can be easily obtained. In particular, when an N- (1-benzyl-3-pyrrolidinyl) glycine derivative or a salt thereof is obtained from a general-purpose and readily available 1-benzyl-3-aminopyrrolidine derivative or a salt thereof, various fields including the pharmaceutical field Thus, an N- (3-pyrrolidinyl) glycine derivative that is important in production can be produced particularly easily. Moreover, since handling is also easy, it is advantageous on industrial production.
　以下、本発明を詳述する。 Hereinafter, the present invention will be described in detail.
　本発明の製造方法は、基本的に、以下の反応式に従って
（ａ）一般式（１）で表される１－ベンジル－３－アミノピロリジン誘導体を一般式（３）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体に変換する工程、
（ｂ）これを一般式（４）で表されるＮ－（３－ピロリジニル）グリシン誘導体に変換する工程、からなる。ただし、例えば、工程（ｂ）において、必ずしも工程(ａ)の方法により得られた化合物を用いる必要はなく、その他方法により得られたものを用いてもよく、それぞれの工程を別個独立に行ってもよい。この２つの工程を以下順を追って詳細に説明する。 The production method of the present invention basically comprises (a) a 1-benzyl-3-aminopyrrolidine derivative represented by the general formula (1) according to the following reaction formula. Converting to 1-benzyl-3-pyrrolidinyl) glycine derivative;
(B) a step of converting this into an N- (3-pyrrolidinyl) glycine derivative represented by the general formula (4). However, for example, in the step (b), it is not always necessary to use the compound obtained by the method of the step (a), and those obtained by other methods may be used, and each step is performed independently. Also good. These two steps will be described in detail below in order.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　１．工程（ａ）
　本工程（ａ）においては、前記式（１）で表される１－ベンジル－３－アミノピロリジン誘導体、又はその塩（以下、化合物（１）とも称する）に、一般式（２）： 1. Step (a)
In this step (a), the 1-benzyl-3-aminopyrrolidine derivative represented by the formula (1) or a salt thereof (hereinafter also referred to as the compound (1)) is added to the general formula (2):
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で表される化合物（以下、化合物（２）とも称する）を反応させることにより、前記式（３）で表される（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩を調製する。 (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the above formula (3) or a salt thereof is prepared by reacting the compound represented by formula (hereinafter also referred to as compound (2)).
　上記一般式（１）および（３）において、Ｒ１は水素原子、ベンジル基を表す。好ましくは水素原子である。このような化合物は、一般的に入手容易であり、原料として使用するのに適している。このような化合物を用いた場合、後述するように、保護や脱保護を行うことなく水素添加のみで目的化合物を合成出来る。 In the above general formulas (1) and (3), R 1 represents a hydrogen atom or a benzyl group. Preferably it is a hydrogen atom. Such compounds are generally readily available and are suitable for use as raw materials. When such a compound is used, the target compound can be synthesized only by hydrogenation without protection or deprotection, as described later.
　上記一般式（２）および（３）において、Ｒ２は、炭素数１～２０の置換されていても良いアルキル基、炭素数２～２０の置換されていても良いアルケニル基、炭素数７～２０の置換されていても良いアラルキル基、炭素数６～２０の置換されていても良いアリール基、水素原子、又はアルカリ金属を表す。 In the above general formulas (2) and (3), R 2 represents an alkyl group which may be substituted having 1 to 20 carbon atoms, an alkenyl group which may be substituted having 2 to 20 carbon atoms, or 7 to 7 carbon atoms. 20 represents an optionally substituted aralkyl group, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal.
　好ましくは、メチル基、エチル基、イソプロピル基、ｔｅｒｔ－ブチル基、ｎ－オクチル基、ヒドロキシメチル基、クロロメチル基、ベンジル基、フェニル基、ビニル基、アリル基、水素原子、ナトリウム、カリウム、リチウム等を挙げることが出来るが、これらに限定されるものではない。より好ましくはメチル基、エチル基、イソプロピル基、ｔｅｒｔ－ブチル基、水素原子、ナトリウム、又はカリウムである。特に好ましくはメチル基、又はエチル基である。 Preferably, methyl group, ethyl group, isopropyl group, tert-butyl group, n-octyl group, hydroxymethyl group, chloromethyl group, benzyl group, phenyl group, vinyl group, allyl group, hydrogen atom, sodium, potassium, lithium However, it is not limited to these. More preferred are methyl group, ethyl group, isopropyl group, tert-butyl group, hydrogen atom, sodium or potassium. Particularly preferred is a methyl group or an ethyl group.
　一般式（１）および（３）において、＊は不斉炭素原子を表す。不斉炭素原子の立体配置はそれぞれ（Ｒ）、（Ｓ）のいずれでもよく、両対掌体の内、一方がわずかに過剰であるものも本発明に含まれる。 In general formulas (1) and (3), * represents an asymmetric carbon atom. The configuration of the asymmetric carbon atom may be either (R) or (S), and one of both enantiomers that is slightly excessive is also included in the present invention.
　また本反応において、不斉炭素原子の立体配置は保持される。すなわち上記一般式（１）の立体配置が（Ｒ）であるとき、一般式（３）の立体配置は（Ｒ）であり、又一般式（１）の立体配置が（Ｓ）であるとき、一般式（３）の立体配置は（Ｓ）である。 In this reaction, the configuration of the asymmetric carbon atom is retained. That is, when the configuration of the general formula (1) is (R), the configuration of the general formula (3) is (R), and when the configuration of the general formula (1) is (S), The configuration of general formula (3) is (S).
　また上記一般式（１）および（３）は、酸との塩の形態でも同様に使用できる。酸としては、一般的な無機酸又は有機酸が挙げられる。具体的には塩化水素、臭化水素、硫酸、硝酸、燐酸等の無機酸類；メタンスルホン酸、ｐ－トルエンスルホン酸、酢酸、トリフルオロ酢酸、クエン酸、蟻酸等の有機酸類等を挙げることができるが、これらに限定されるものではない。 The above general formulas (1) and (3) can also be used in the form of a salt with an acid. Examples of the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these.
　また上記一般式（２）において、Ｘは脱離基を表す。脱離基としては、特に制限はないが、ハロゲン原子、スルホニルオキシ基、ホスホリルオキシ基等が挙げられる。具体的には、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子であり、スルホニルオキシ基としては、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基、ｍ－ニトロベンゼンスルホニルオキシ基、フルオロスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等であり、ホスホリルオキシ基としては、メチルホスホリルオキシ基、エチルホスホリルオキシ基、フェニルホスホリルオキシ基等などであるが、これらに限定されるものではない。好ましくはハロゲン原子であり、更に好ましくは塩素原子、又は臭素原子である。 In the general formula (2), X represents a leaving group. The leaving group is not particularly limited, and examples thereof include a halogen atom, a sulfonyloxy group, and a phosphoryloxy group. Specifically, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the sulfonyloxy group is a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, m-nitrobenzene. A sulfonyloxy group, a fluorosulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like, and examples of the phosphoryloxy group include a methylphosphoryloxy group, an ethylphosphoryloxy group, and a phenylphosphoryloxy group, but are not limited thereto. is not. Preferably it is a halogen atom, More preferably, it is a chlorine atom or a bromine atom.
　化合物（２）の使用量は特に制限はないが、化合物（１）に対して通常０．５～３．０倍モル量であるが、好ましくは０．８～２．０倍モル量であり、より好ましくは１．０～１．５倍モル量である。 The amount of compound (2) to be used is not particularly limited, but is usually 0.5 to 3.0-fold mol amount, preferably 0.8 to 2.0-fold mol amount based on compound (1). More preferably, the molar amount is 1.0 to 1.5 times.
　本工程（ａ）において、必要に応じて塩基を添加してもよい。使用される塩基としては特に限定されず、例えば、リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、塩化マグネシウムジイソプロピルアミド等の金属アミド；メチルリチウム、ｎ－ブチルリチウム等の有機リチウム試薬；臭化メチルマグネシウム、塩化ｔｅｒｔ－ブチルマグネシウム等のグリニャール試薬；ナトリウムメトキシド、マグネシウムエトキシド、カリウムｔｅｒｔ－ブトキシド等の金属アルコキシド；水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム等の金属水素化物等；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸カルシウム、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素セシウムなどの炭酸金属塩；水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の金属水酸化物；酢酸リチウム、酢酸ナトリウム、酢酸カリウム等の酢酸金属塩；トリエチルアミン、エチルジイソプロピルアミン、ピリジン等の有機塩基を挙げることができるが、これらに限定されるものではない。好ましくは、金属水素化物、炭酸金属塩、有機塩基であり、より好ましくは炭酸ナトリウム、炭酸カリウム、トリエチルアミン、エチルジイソプロピルアミン、ピリジンであり、特に好ましくはトリエチルアミンである。 In this step (a), a base may be added as necessary. The base used is not particularly limited, and examples thereof include metal amides such as lithium amide, sodium amide, lithium diisopropylamide, and magnesium chloride diisopropylamide; organolithium reagents such as methyllithium and n-butyllithium; methylmagnesium bromide, Grignard reagents such as tert-butylmagnesium chloride; metal alkoxides such as sodium methoxide, magnesium ethoxide and potassium tert-butoxide; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; Lithium, sodium carbonate, potassium carbonate, sodium carbonate, calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, etc .; lithium hydroxide, hydroxide Metal hydroxides such as thorium and potassium hydroxide; metal acetates such as lithium acetate, sodium acetate, and potassium acetate; organic bases such as triethylamine, ethyldiisopropylamine, and pyridine can be mentioned, but are not limited thereto is not. Preferred are metal hydrides, metal carbonates and organic bases, more preferred are sodium carbonate, potassium carbonate, triethylamine, ethyldiisopropylamine and pyridine, and particularly preferred is triethylamine.
　塩基の使用量は特に制限はないが、化合物（１）に対して通常０．５～４．０倍モル量であるが、好ましくは０．８～３．０倍モル量であり、より好ましくは１．０～２．０倍モル量である。 The amount of the base used is not particularly limited, but is usually 0.5 to 4.0 times the molar amount relative to the compound (1), preferably 0.8 to 3.0 times the molar amount, and more preferably Is 1.0 to 2.0 times the molar amount.
　本工程において、反応溶媒は特に必要としないが、反応基質によっては反応溶媒を使用してもよく、その場合反応溶媒種に特に制限はない。反応に用いられる反応溶媒は、水、有機溶媒、または水と有機溶媒の混合溶媒である。 In this step, a reaction solvent is not particularly required, but depending on the reaction substrate, a reaction solvent may be used. The reaction solvent used for the reaction is water, an organic solvent, or a mixed solvent of water and an organic solvent.
　有機溶媒としては特に限定されず、例えば、メタノール、エタノール、ｎ－ブタノール、イソプロパノール、エチレングリコール、メトキシアルコール等のアルコール系溶媒；ベンゼン、トルエン、ｎ－ヘキサン、シクロヘキサン等の炭化水素系溶媒；ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、メチルｔｅｒｔ－ブチルエーテル、ジメトキシエタン、エチレングリコールジメチルエーテル等のエーテル系溶媒；酢酸エチル、酢酸ブチル等のエステル系溶媒；アセトン、メチルエチルケトン等のケトン系溶媒；塩化メチレン、クロロホルム、１，１，１－トリクロロエタン等のハロゲン系溶媒；アセトニトリル、アセトアミド、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン等の含窒素系溶媒；ジメチルスルホキシド、ヘキサメチル燐酸トリアミド等の非プロトン性極性溶媒等を挙げることができる。これらは単独で用いても良く、２種類以上を併用してもよい。好ましくは、炭化水素系溶媒、エーテル系溶媒、エステル系溶媒、ケトン系溶媒である。 The organic solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol, ethanol, n-butanol, isopropanol, ethylene glycol, and methoxy alcohol; hydrocarbon solvents such as benzene, toluene, n-hexane, and cyclohexane; diethyl ether , Tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether, and other ether solvents; ethyl acetate, butyl acetate, and other ester solvents; acetone, methyl ethyl ketone, and other ketone solvents; methylene chloride, chloroform Halogen-based solvents such as 1,1,1-trichloroethane; nitrogen-containing solvents such as acetonitrile, acetamide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone; Methyl sulfoxide, aprotic polar solvents such as hexamethylphosphoric acid triamide, and the like. These may be used alone or in combination of two or more. Preferred are hydrocarbon solvents, ether solvents, ester solvents, and ketone solvents.
　本工程の反応温度としては特に制限はないが、－３０℃～１６０℃が好ましく、より好ましくは－２０℃～５０℃である。特に好ましくは０～３０℃である。 The reaction temperature in this step is not particularly limited, but is preferably −30 ° C. to 160 ° C., more preferably −20 ° C. to 50 ° C. Particularly preferred is 0 to 30 ° C.
　本工程（ａ）において反応手順は特に限定されず、全ての試剤を一括添加するだけでよいが、化合物（１）の溶液に、塩基を加え、その後化合物（２）を加えるとよい。 In this step (a), the reaction procedure is not particularly limited, and all the reagents may be added at once. However, a base is added to the solution of compound (1), and then compound (2) is added.
　反応終了後、得られた反応液をそのまま次工程に供しても良いが、反応液から生成物を取得するためには、一般的な後処理を行えばよい。例えば、反応終了後、反応液のｐＨを必要に応じて調整し、酢酸エチル、ジエチルエーテル、塩化メチレン、トルエン、ヘキサン等の一般的な抽出溶媒を用いて抽出操作を行う。得られた抽出液から、減圧加熱等の操作により反応溶媒および抽出溶媒を留去すると、目的物が得られる。また、反応終了後、直ちに減圧加熱等の操作により反応溶媒を留去してから同様の操作を行ってもよいし、必要に応じて水を添加したのち、反応溶媒を留去してもよい。又は反応終了後、所定の温度で反応液のｐＨを調製し析出した結晶を濾過してもよい。 After completion of the reaction, the obtained reaction solution may be used for the next step as it is, but in order to obtain a product from the reaction solution, general post-treatment may be performed. For example, after completion of the reaction, the pH of the reaction solution is adjusted as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. In addition, immediately after completion of the reaction, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and then the same operation may be performed, or after adding water as necessary, the reaction solvent may be distilled off. . Alternatively, after completion of the reaction, the pH of the reaction solution may be adjusted at a predetermined temperature and the precipitated crystals may be filtered.
　このようにして得られる目的物は、ほぼ純粋なものであるが、晶析精製、分別蒸留、カラムクロマトグラフィー等の一般的な手法により精製を行い、さらに純度を高めてもよい。得られた目的物は、乾燥機等を使用し乾燥を行っても良い。 The target product thus obtained is almost pure, but it may be further purified by a general technique such as crystallization purification, fractional distillation, column chromatography, etc. The obtained object may be dried using a dryer or the like.
　上記晶析に用いる溶媒としては特に制限はなく、例えばペンタン、ヘキサン、ヘプタン、オクタン、水、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、ベンゼン、キシレン、メシチレン、テトラヒドロフラン、テトラヒドロピラン、１，３－ジオキサン、１，４－ジオキサン、酢酸メチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｔｅｒｔ－ブチル、ジメチルエーテル、メチルｔｅｒｔ－ブチルエーテル、アセトニトリル、プロピオニトリル、ブチロニトリル、アセトン、ジメチルスルホキシド、ジメチルアセトアミド、Ｎ－メチルピロリドン、およびこれら２種以上の混合溶媒などを挙げることができる。 The solvent used for the crystallization is not particularly limited. For example, pentane, hexane, heptane, octane, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, benzene, xylene, mesitylene. , Tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, dimethyl ether, methyl tert- Examples include butyl ether, acetonitrile, propionitrile, butyronitrile, acetone, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, and a mixed solvent of two or more of these.
　なお、本工程で得られる前記式（３）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩は、文献未記載の新規化合物である。 The N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the formula (3) obtained in this step or a salt thereof is a novel compound not described in any literature.
　２．工程（ｂ）
　本工程（ｂ）においては、前記式（３）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩（以下、化合物（３）とも称する）を、脱ベンジル化することにより、前記式（４）で表されるＮ－（３－ピロリジニル）グリシン誘導体、又はその塩を調製する。 2. Step (b)
In this step (b), the N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the above formula (3) or a salt thereof (hereinafter also referred to as compound (3)) is debenzylated. Thus, an N- (3-pyrrolidinyl) glycine derivative represented by the above formula (4) or a salt thereof is prepared.
　一般式（３）および（４）において、＊は不斉炭素原子をあらわす。不斉炭素原子の立体配置はそれぞれ（Ｒ）、（Ｓ）のいずれでもよく、両対掌体の内、一方がわずかに過剰であるものも本発明に含まれる。 In general formulas (3) and (4), * represents an asymmetric carbon atom. The configuration of the asymmetric carbon atom may be either (R) or (S), and one of both enantiomers that is slightly excessive is also included in the present invention.
　また反応において、不斉炭素原子の立体配置は保持される。すなわち上記一般式（３）の立体配置が（Ｒ）であるとき、一般式（４）の立体配置は（Ｒ）であり、又一般式（３）の立体配置が（Ｓ）であるとき、一般式（４）の立体配置は（Ｓ）である。 In the reaction, the configuration of the asymmetric carbon atom is retained. That is, when the configuration of the general formula (3) is (R), the configuration of the general formula (4) is (R), and when the configuration of the general formula (3) is (S), The configuration of the general formula (4) is (S).
　また上記一般式（３）および（４）は、酸との塩の形態でも同様に使用できる。酸としては、一般的な無機酸又は有機酸が挙げられる。具体的には塩化水素、臭化水素、硫酸、硝酸、燐酸等の無機酸類；メタンスルホン酸、ｐ－トルエンスルホン酸、酢酸、トリフルオロ酢酸、クエン酸、蟻酸等の有機酸類等を挙げることができるが、これらに限定されるものではない。 The above general formulas (3) and (4) can also be used in the form of a salt with an acid. Examples of the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these.
　上記脱ベンジル化する方法としては、特に限定されないが、好ましくは、塩酸、硫酸等で加水分解する方法、クロロ炭酸アリル、クロロ炭酸エチル等と反応した後、加水分解する方法、遷移金属触媒存在下で水素化する方法である。更に好ましくは、遷移金属触媒存在下で水素化する方法である。 The method for debenzylation is not particularly limited, but preferably a method of hydrolysis with hydrochloric acid, sulfuric acid, etc., a method of hydrolysis after reacting with allyl chlorocarbonate, ethyl chlorocarbonate, etc., in the presence of a transition metal catalyst. This is a method of hydrogenation. More preferred is a method of hydrogenation in the presence of a transition metal catalyst.
　上記方法で用いられる遷移金属触媒としては、例えば、白金、ロジウム、パラジウム、ニッケル、ルテニウム、イリジウム、又はレニウム等の金属、合金、もしくはその塩化物等が挙げられる。 Examples of the transition metal catalyst used in the above method include metals such as platinum, rhodium, palladium, nickel, ruthenium, iridium, rhenium, alloys, and chlorides thereof.
　またこれらの触媒は、触媒活性、再現性、保存安定性、操作性、リサイクルの観点から、粉末担体に分散させた触媒を用いる方が好ましい。 In addition, it is preferable to use a catalyst dispersed in a powder carrier from the viewpoints of catalyst activity, reproducibility, storage stability, operability, and recycling.
　粉末担体としては、例えば、炭素、アルミナ、シリカーアルミナ、シリカ、炭酸バリウム、硫酸バリウム、炭酸カルシウム、酸化チタン、酸化ジルコニウム、又はゼオライト等が挙げられ、好ましくは、これら粉末担体に担持された白金、ロジウム、又はパラジウムの金属、若しくはその硫化物、又は水酸化物等である。具体的には、例えば白金－炭素、白金（ＩＩ）スルフィド－炭素、白金－アルミナ、白金－シリカーアルミナ、白金－シリカ、白金－炭酸バリウム、白金－硫酸バリウム、白金－炭酸カルシウム、白金－酸化チタン、白金－酸化ジルコニウム、白金－ゼオライト、白金－アスベスト、白金ロジウム合金－炭素、白金パラジウム合金－炭素、ロジウム－炭素、ロジウム－アルミナ、ロジウム－シリカ、ロジウム－炭酸カルシウム、パラジウム－炭素、水酸化パラジウム（ＩＩ）－炭素、パラジウム（ＩＩ）スルフィド－炭素、パラジウム－アルミナ、パラジウム－シリカーアルミナ、パラジウム－シリカ、パラジウム－炭酸バリウム、パラジウム－硫酸バリウム、パラジウム－炭酸カルシウム、パラジウム－酸化チタン、パラジウム－酸化ジルコニウム、パラジウム－ゼオライト、パラジウム－アスベスト、ルテニウム－炭素、ルテニウム－アルミナ、ルテニウム－シリカ、ルテニウム－炭酸カルシウム、イリジウム－炭素、イリジウム－アルミナ、イリジウム－シリカ、イリジウム－炭酸カルシウム等が挙げられる。 Examples of the powder carrier include carbon, alumina, silica-alumina, silica, barium carbonate, barium sulfate, calcium carbonate, titanium oxide, zirconium oxide, and zeolite, and preferably platinum supported on these powder carriers. , Rhodium, or palladium metal, sulfide thereof, or hydroxide. Specifically, for example, platinum-carbon, platinum (II) sulfide-carbon, platinum-alumina, platinum-silica-alumina, platinum-silica, platinum-barium carbonate, platinum-barium sulfate, platinum-calcium carbonate, platinum-oxidation Titanium, platinum-zirconium oxide, platinum-zeolite, platinum-asbestos, platinum rhodium alloy-carbon, platinum palladium alloy-carbon, rhodium-carbon, rhodium-alumina, rhodium-silica, rhodium-calcium carbonate, palladium-carbon, hydroxylation Palladium (II) -carbon, palladium (II) sulfide-carbon, palladium-alumina, palladium-silica-alumina, palladium-silica, palladium-barium carbonate, palladium-barium sulfate, palladium-calcium carbonate, palladium-titanium oxide, palladium -Zill oxide Chloride, palladium - zeolite, palladium - asbestos, ruthenium - carbon, ruthenium - alumina, ruthenium - silica, ruthenium - calcium carbonate, iridium - carbon, iridium - alumina, iridium - silica, iridium - calcium carbonate.
　またこれらの遷移金属触媒は、単独で用いてもよく、２種以上を併用してもよい。好ましくは、パラジウム－炭素、ロジウム－炭素、白金－炭素、又は水酸化パラジウム（ＩＩ）－炭素であり、更に好ましくはパラジウム－炭素、又は水酸化パラジウム（ＩＩ）－炭素であり、特に好ましくは水酸化パラジウム（ＩＩ）－炭素である。 These transition metal catalysts may be used alone or in combination of two or more. Preferred is palladium-carbon, rhodium-carbon, platinum-carbon or palladium hydroxide (II) -carbon, more preferred is palladium-carbon or palladium (II) -carbon, and particularly preferred is water. Palladium (II) oxide-carbon.
　上記遷移金属触媒の使用量としては多すぎるとコストや後処理の点で好ましくないため、上記化合物（３）に対して、好ましくは５倍重量以下であり、更に好ましくは０．０１～０．５倍重量である。 When the amount of the transition metal catalyst used is too large, it is not preferable from the viewpoint of cost and post-treatment, and therefore it is preferably 5 times or less by weight with respect to the compound (3), more preferably 0.01 to 0.00. 5 times the weight.
　本工程は、反応溶媒を特に必要としないが、反応基質によっては反応溶媒を使用してもよく、その場合反応溶媒種に特に制限はない。反応に用いられる反応溶媒は、水、有機溶媒、または水と有機溶媒の混合溶媒である。 This step does not particularly require a reaction solvent, but a reaction solvent may be used depending on the reaction substrate, and in that case, there is no particular limitation on the type of reaction solvent. The reaction solvent used for the reaction is water, an organic solvent, or a mixed solvent of water and an organic solvent.
　上記有機溶媒としては特に限定されず、例えば、メタノール、エタノール、ｎ－ブタノール、イソプロパノール、エチレングリコール、メトキシアルコール等のアルコール系溶媒；ベンゼン、トルエン、ｎ－ヘキサン、シクロヘキサン等の炭化水素系溶媒；ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、メチルｔｅｒｔ－ブチルエーテル、ジメトキシエタン、エチレングリコールジメチルエーテル等のエーテル系溶媒；酢酸エチル、酢酸ブチル等のエステル系溶媒；アセトン、メチルエチルケトン等のケトン系溶媒；塩化メチレン、クロロホルム、１，１，１－トリクロロエタン等のハロゲン系溶媒；アセトニトリル、アセトアミド、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン、等の含窒素系溶媒；ジメチルスルホキシド、ヘキサメチル燐酸トリアミド等の非プロトン性極性溶媒等を挙げることができる。これらは単独で用いても良く、２種類以上を併用してもよい。好ましくは、アルコール系溶媒、炭化水素系溶媒、エーテル系溶媒、エステル系溶媒である。より好ましくはアルコール系溶媒である。 The organic solvent is not particularly limited, and examples thereof include alcohol solvents such as methanol, ethanol, n-butanol, isopropanol, ethylene glycol, and methoxy alcohol; hydrocarbon solvents such as benzene, toluene, n-hexane, and cyclohexane; diethyl Ether solvents such as ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; methylene chloride, Halogen-based solvents such as chloroform and 1,1,1-trichloroethane; nitrogen-containing systems such as acetonitrile, acetamide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone Medium; dimethyl sulfoxide, may be mentioned aprotic polar solvents such as hexamethylphosphoric triamide. These may be used alone or in combination of two or more. Alcohol solvents, hydrocarbon solvents, ether solvents, and ester solvents are preferable. More preferred is an alcohol solvent.
　また、本工程における水素圧は、好ましくは５０バール以下であり、更に好ましくは１～１０バールである。 Also, the hydrogen pressure in this step is preferably 50 bar or less, more preferably 1 to 10 bar.
　本工程における反応温度としては、特に制限はないが、－３０℃～１６０℃が好ましく、より好ましくは０℃～５０℃である。特に好ましくは０～３０℃である。 The reaction temperature in this step is not particularly limited, but is preferably −30 ° C. to 160 ° C., more preferably 0 ° C. to 50 ° C. Particularly preferred is 0 to 30 ° C.
　本反応は、反応の速度を向上させる目的で、更に酸を添加して行うとよい。酸としては、一般的な無機酸又は有機酸が挙げられる。具体的には塩化水素、臭化水素、硫酸、硝酸、燐酸等の無機酸類；メタンスルホン酸、ｐ－トルエンスルホン酸、酢酸、トリフルオロ酢酸、クエン酸、蟻酸等の有機酸類等を挙げることができるが、これらに限定されるものではない。好ましくは無機酸であり、更に好ましくは塩化水素、又は硫酸である。 This reaction may be carried out by further adding an acid for the purpose of improving the reaction rate. Examples of the acid include general inorganic acids or organic acids. Specific examples include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid and formic acid. However, it is not limited to these. An inorganic acid is preferable, and hydrogen chloride or sulfuric acid is more preferable.
　本工程（ｂ）において反応手順は特に限定されず、全ての試剤を一括添加するだけでよいが、通常、上記化合物（３）の溶液に、必要に応じて酸を加え、その後遷移金属触媒を添加し、更に水素ガスを加えればよい。 In this step (b), the reaction procedure is not particularly limited, and it is only necessary to add all reagents at once. Usually, an acid is added to the solution of the compound (3) as necessary, and then a transition metal catalyst is added. It is only necessary to add hydrogen gas.
　反応後の後処理としては、反応液から生成物を取得するための一般的な処理を行えばよい。例えば、反応終了後の反応液から触媒を濾別し、濾液から減圧加熱等の操作により反応溶媒を留去すると目的物が得られる。 As the post-treatment after the reaction, a general treatment for obtaining a product from the reaction solution may be performed. For example, the target product can be obtained by filtering the catalyst from the reaction solution after completion of the reaction and distilling the reaction solvent from the filtrate by operation such as heating under reduced pressure.
　このようにして得られる目的物は、ほぼ純粋なものであるが、晶析精製、分別蒸留、カラムクロマトグラフィー等の一般的な手法により精製を加え、さらに純度を高めてもよい。得られた目的物は、乾燥機等を使用し乾燥を行っても良い。 The target product thus obtained is almost pure, but the purity may be further increased by adding purification by general techniques such as crystallization purification, fractional distillation, column chromatography and the like. The obtained object may be dried using a dryer or the like.
　上記晶析に用いる溶媒としては化合物により異なるため特に制限はなく、例えばペンタン、ヘキサン、ヘプタン、オクタン、水、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、イソブタノール、ｔｅｒｔ－ブタノール、ベンゼン、キシレン、メシチレン、テトラヒドロフラン、テトラヒドロピラン、１，３－ジオキサン、１，４－ジオキサン、酢酸メチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｔｅｒｔ－ブチル、ジメチルエーテル、メチルｔｅｒｔ－ブチルエーテル、アセトニトリル、プロピオニトリル、ブチロニトリル、アセトン、ジメチルスルホキシド、ジメチルアセトアミド、Ｎ－メチルピロリドン、およびこれら２種以上の混合溶媒などを挙げることができる。 The solvent used for the crystallization is not particularly limited because it varies depending on the compound. For example, pentane, hexane, heptane, octane, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, benzene , Xylene, mesitylene, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, dimethyl ether , Methyl tert-butyl ether, acetonitrile, propionitrile, butyronitrile, acetone, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, and a mixture of two or more of these It can be mentioned.
　なお本工程で得られる前記式（４）で表されるＮ－（３－ピロリジニル）グリシン誘導体、又はその塩は、文献未記載の新規化合物である。 The N- (3-pyrrolidinyl) glycine derivative represented by the formula (4) obtained in this step or a salt thereof is a novel compound not described in any literature.
　また上記の方法により製造した、Ｎ－（３－ピロリジニル）グリシン誘導体、又はその塩、のアミノ基を必要に応じて保護することにより、所望の各種Ｎ－（３－ピロリジニル）グリシン誘導体を調製することができる。 Further, various desired N- (3-pyrrolidinyl) glycine derivatives are prepared by protecting the amino group of the N- (3-pyrrolidinyl) glycine derivative, or a salt thereof, produced by the above method, if necessary. be able to.
　保護基、及び保護方法としては、例えばPROTECTIVE GROUPS in ORGANIC SYNTHESIS pp.503-659に記載された保護基、保護方法等が挙げられる。 Examples of the protecting group and the protecting method include protecting groups and protecting methods described in PROTECTIVEECTGROUPS in ORGANIC SYNTHESIS pp.503-659.
　以下に例を挙げて本発明を更に詳しく説明するが、本発明はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
　（実施例１）Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル Example 1 N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　（Ｒ）－１－ベンジル－３－アミノピロリジン２．０ｇ（１１ｍｍｏｌ）をジクロロメタン２０ｍｌに溶かした溶液に、トリエチルアミン３．１ｍｌ（２３ｍｍｏｌ）、ブロモ酢酸エチル１．９ｍｌ（１７ｍｍｏｌ）を加え、室温で１７時間攪拌した。反応溶液に水２０ｍｌを加え、酢酸エチル８０ｍｌで抽出した。有機層を水２０ｍｌで洗浄した後、減圧下に濃縮し、粗生成物２．４ｇを取得した。粗生成物をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）により精製し、Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル２．１ｇ（収率７３％）を得た。 To a solution of (R) -1-benzyl-3-aminopyrrolidine (2.0 g, 11 mmol) in dichloromethane (20 ml) was added triethylamine (3.1 ml, 23 mmol) and ethyl bromoacetate (1.9 ml, 17 mmol). Stir for hours. 20 ml of water was added to the reaction solution, and extracted with 80 ml of ethyl acetate. The organic layer was washed with 20 ml of water and then concentrated under reduced pressure to obtain 2.4 g of a crude product. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 2.1 g (73% yield) of N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester.
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３Ｃｌ）
δ７．３１－７．１０（５Ｈ，ｍ），４．２０－４．１５（２Ｈ，ｑ），３．６３－３．５６（２Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．３４－３．２５（１Ｈ，ｍ），２．７５－２．７１（１Ｈ，ｍ），２．６４－２．６１（１Ｈ，ｍ），２．５６－２．５３（１Ｈ，ｍ），２．３６－２．３２（１Ｈ，ｍ），２．１５－２．０５（１Ｈ，ｍ），１．６３－１．５５（１Ｈ，ｍ），１．２８－１．２４（３Ｈ，ｔ）。 1 H-NMR (400 MHz, CD 3 Cl)
δ 7.31-7.10 (5H, m), 4.20-4.15 (2H, q), 3.63-3.56 (2H, m), 3.35 (2H, s), 3. 34-3.25 (1H, m), 2.75-2.71 (1H, m), 2.64-2.61 (1H, m), 2.56-2.53 (1H, m), 2.36-2.32 (1H, m), 2.15-2.05 (1H, m), 1.63-1.55 (1H, m), 1.28-1.24 (3H, t ).
　（実施例２）Ｎ－（（Ｒ）－３－ピロリジニル）グリシンエチルエステル Example 2 N-((R) -3-pyrrolidinyl) glycine ethyl ester
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル４９０ｍｇ（１．８ｍｍｏｌ）をエタノール５ｍｌに溶かした溶液に、濃塩酸５２０ｍｇ（５．３ｍｍｏｌ）、５％Ｐｄ－Ｃ（５０％含水）１００ｍｇを添加した。水素置換を行い、室温で１７時間攪拌した。反応溶液からＰｄ－Ｃを濾別し、エタノール５ｍｌで洗浄した。濾過液を減圧下に濃縮し、Ｎ－（（Ｒ）－３－ピロリジニル）グリシンエチルエステル６５０ｍｇ（収率９２％）を取得した。 To a solution of 490 mg (1.8 mmol) of N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester in 5 ml of ethanol, 520 mg of concentrated hydrochloric acid (5.3 mmol), 5% Pd—C (50% 100 mg of water) was added. Hydrogen substitution was performed and the mixture was stirred at room temperature for 17 hours. Pd—C was filtered off from the reaction solution and washed with 5 ml of ethanol. The filtrate was concentrated under reduced pressure to obtain 650 mg (yield 92%) of N-((R) -3-pyrrolidinyl) glycine ethyl ester.
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ４．２５－４．２１（２Ｈ，ｑ），４．１０－４．０５（２Ｈ，ｓ），３．９６－３．９３（１Ｈ，ｍ），３．２７－３．１９（１Ｈ，ｍ），２．３０－２．１９（２Ｈ，ｍ），１．２７－１．１９（３Ｈ，ｔ）。 1 H-NMR (400 MHz, DMSO-d6)
δ 4.25-4.21 (2H, q), 4.10-4.05 (2H, s), 3.96-3.93 (1H, m), 3.27-3.19 (1H, m ), 2.30-2.19 (2H, m), 1.27-1.19 (3H, t).
　（実施例３）Ｎ－ベンジル－Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル Example 3 N-Benzyl-N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　（Ｒ）－１－ベンジル－３－Ｎ－ベンジルアミノピロリジン２００ｍｇ（０．７５ｍｍｏｌ）をＴＨＦ２ｍｌに溶かした溶液に、トリエチルアミン０．２ｍｌ（１．５ｍｍｏｌ）、ブロモ酢酸エチル０．１３ｍｌ（１．１ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応溶液に水５ｍｌを加え、酢酸エチル４０ｍｌで抽出した。有機層を水５ｍｌで洗浄した後、減圧下に濃縮し、粗生成物２４２ｍｇを取得した。粗生成物をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）により精製し、Ｎ－ベンジル－Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル２３２ｍｇ（収率６６％）を得た。 (R) -1-Benzyl-3-N-benzylaminopyrrolidine 200 mg (0.75 mmol) dissolved in 2 ml of THF was added to 0.2 ml (1.5 mmol) of triethylamine and 0.13 ml (1.1 mmol) of ethyl bromoacetate. And stirred at room temperature for 18 hours. 5 ml of water was added to the reaction solution, and extracted with 40 ml of ethyl acetate. The organic layer was washed with 5 ml of water and then concentrated under reduced pressure to obtain 242 mg of a crude product. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 232 mg (yield 66%) of N-benzyl-N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester. It was.
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３Ｃｌ）
δ７．３３－７．２０（１０Ｈ，ｍ），４．１２－４．０７（２Ｈ，ｑ），３．８１－３．７２（２Ｈ，ｍ），３．６３－３．５２（３Ｈ，ｍ），３．４０－３．３０（２Ｈ，ｍ），２．７０－２．４０（４Ｈ，ｍ），２．０８－１．９９（１Ｈ，ｍ），１．８４－１．７６（１Ｈ，ｍ），１．２６－１．２１（３Ｈ，ｔ）。 1 H-NMR (400 MHz, CD 3 Cl)
δ 7.33-7.20 (10H, m), 4.12-4.07 (2H, q), 3.81-3.72 (2H, m), 3.63-3.52 (3H, m ), 3.40-3.30 (2H, m), 2.70-2.40 (4H, m), 2.08-1.99 (1H, m), 1.84-1.76 (1H) , M), 1.26-1.21 (3H, t).
　（実施例４）Ｎ－（（Ｒ）－３－ピロリジニル）グリシンエチルエステル
　Ｎ－ベンジル－Ｎ－（（３Ｒ）－１－ベンジル－３－ピロリジニル）グリシンエチルエステル８８ｍｇ（０．２５ｍｍｏｌ）をエタノール２ｍｌに溶かした溶液に、濃塩酸７４ｍｇ（０．７５ｍｍｏｌ）、５％Ｐｄ－Ｃ（５０％含水）３４ｍｇを添加した。水素置換を行い、室温で１７時間攪拌した。反応溶液からＰｄ－Ｃを濾別し、エタノール５ｍｌで洗浄した。濾過液を減圧下に濃縮し、Ｎ－（（Ｒ）－３－ピロリジニル）グリシンエチルエステル５０ｍｇ（収率９２％）を取得した。 Example 4 N-((R) -3-pyrrolidinyl) glycine ethyl ester N-benzyl-N-((3R) -1-benzyl-3-pyrrolidinyl) glycine ethyl ester 88 mg (0.25 mmol) was added to 2 ml of ethanol. Concentrated hydrochloric acid 74 mg (0.75 mmol) and 5% Pd—C (containing 50% water) 34 mg were added to the solution dissolved in. Hydrogen substitution was performed and the mixture was stirred at room temperature for 17 hours. Pd—C was filtered off from the reaction solution and washed with 5 ml of ethanol. The filtrate was concentrated under reduced pressure to obtain 50 mg (yield 92%) of N-((R) -3-pyrrolidinyl) glycine ethyl ester.
　（参考例１）Ｎ－（（３Ｒ）－１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピロリジニル）グリシンエチルエステル Reference Example 1 N-((3R) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl) glycine ethyl ester
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　Ｎ－（（Ｒ）－３－ピロリジニル）グリシンエチルエステル２５ｍｇ（０．１５ｍｍｏｌ）をテトラヒドロフラン２ｍｌに溶かした溶液に、トリエチルアミン０．１３ｍｌ（０．９ｍｍｏｌ）を添加した。室温でニ炭酸ジｔｅｒｔ－ブチル３７ｍｇ（０．１７ｍｍｏｌ）をゆっくり滴下し、室温で１４時間攪拌した。反応液に水５ｍｌを加え、酢酸エチル１５ｍｌで抽出した。有機層を水５ｍｌで洗浄後、減圧下に濃縮し、Ｎ－（（３Ｒ）－１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピロリジニル）グリシンエチルエステル２５ｍｇ（収率６１％）を得た。 0.13 ml (0.9 mmol) of triethylamine was added to a solution of 25 mg (0.15 mmol) of N-((R) -3-pyrrolidinyl) glycine ethyl ester in 2 ml of tetrahydrofuran. At room temperature, 37 mg (0.17 mmol) of ditert-butyl dicarbonate was slowly added dropwise and stirred at room temperature for 14 hours. 5 ml of water was added to the reaction solution, and extracted with 15 ml of ethyl acetate. The organic layer was washed with 5 ml of water and then concentrated under reduced pressure to obtain 25 mg (61% yield) of N-((3R) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl) glycine ethyl ester.
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３Ｃｌ）
δ４．２１－４．１１（２Ｈ，ｍ），３．８５－３．２０（５Ｈ，ｍ），２．０１（１Ｈ，ｍ），１．８６（２Ｈ，ｍ），１．４５（９Ｈ，ｓ），１．２７－１．２４（３Ｈ，ｍ）。 1 H-NMR (400 MHz, CD 3 Cl)
δ 4.21-4.11 (2H, m), 3.85-3.20 (5H, m), 2.01 (1H, m), 1.86 (2H, m), 1.45 (9H, s), 1.27-1.24 (3H, m).

Claims (5)

  1. 一般式（３）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒ１は水素原子、又はベンジル基を表す。Ｒ２は、炭素数１～２０の置換されていても良いアルキル基、炭素数２～２０の置換されていても良いアルケニル基、炭素数７～２０の置換されていても良いアラルキル基、炭素数６～２０の置換されていても良いアリール基、水素原子、又はアルカリ金属を表す。＊は不斉炭素原子であることを表す。）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩の製造方法であって、
    　一般式（１）：
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ１、＊は前記と同じ）で表される１－ベンジル－３－アミノピロリジン誘導体、又はその塩に、一般式（２）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ２は前記と同じ、Ｘは脱離基を表す。）で表される化合物を反応させることを特徴とする方法。     General formula (3):
    Figure JPOXMLDOC01-appb-C000001
     (Wherein R 1 represents a hydrogen atom or a benzyl group. R 2 represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, Represents an optionally substituted aralkyl group having 7 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal, and * represents an asymmetric carbon atom. A method for producing an N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by the formula:
    General formula (1):
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 1 and * are the same as defined above), a 1-benzyl-3-aminopyrrolidine derivative represented by the formula:
    Figure JPOXMLDOC01-appb-C000003
     (Wherein R 2 is the same as described above, and X represents a leaving group).
  2. Ｒ１が水素原子である請求項１に記載の製造方法。 The production method according to claim 1 , wherein R 1 is a hydrogen atom.
  3. Ｘが塩素原子、又は臭素原子である請求項１又は２に記載の製造方法。 The production method according to claim 1 or 2, wherein X is a chlorine atom or a bromine atom.
  4. 一般式（４）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ２は、炭素数１～２０の置換されていても良いアルキル基、炭素数２～２０の置換されていても良いアルケニル基、炭素数７～２０の置換されていても良いアラルキル基、炭素数６～２０の置換されていても良いアリール基、水素原子、又はアルカリ金属を表す。＊は不斉炭素原子であることを表す。）で表されるＮ－（３－ピロリジニル）グリシン誘導体、又はその塩の製造方法であって、
    　一般式（３）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ１は水素原子、又はベンジル基を表す。Ｒ２、＊は前記に同じ。）で表されるＮ－（１－ベンジル－３－ピロリジニル）グリシン誘導体、又はその塩を、脱ベンジル化することを特徴とする方法。     General formula (4):
    Figure JPOXMLDOC01-appb-C000004
     (In the formula, R 2 is an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, or an optionally substituted alkenyl group having 7 to 20 carbon atoms. An aralkyl group, an optionally substituted aryl group having 6 to 20 carbon atoms, a hydrogen atom, or an alkali metal. * Represents an asymmetric carbon atom.) N- (3-pyrrolidinyl) ) A method for producing a glycine derivative or a salt thereof,
    General formula (3):
    Figure JPOXMLDOC01-appb-C000005
     (Wherein R 1 represents a hydrogen atom or a benzyl group, R 2 and * are the same as defined above), and N- (1-benzyl-3-pyrrolidinyl) glycine derivative represented by A method comprising benzylation.
  5. 前記式（３）の化合物が、請求項１～３のいずれかに記載の方法で得られたことを特徴とする請求項４に記載のＮ－（３－ピロリジニル）グリシン誘導体、又はその塩の製造方法。 The N- (3-pyrrolidinyl) glycine derivative or a salt thereof according to claim 4, wherein the compound of the formula (3) is obtained by the method according to any one of claims 1 to 3. Production method.
PCT/JP2009/052549 2008-02-21 2009-02-16 Process for production of n-(3-pyrrolidinyl)glycine derivative WO2009104557A1 (en)

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US8550346B2 (en) 2010-09-29 2013-10-08 Beijing Mechanical Equipment Institute Low-altitude low-speed small target intercepting method

Citations (3)

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WO2000069432A1 (en) * 1999-05-18 2000-11-23 Teijin Limited Remedies or preventives for diseases in association with chemokines
WO2003045942A2 (en) * 1998-09-04 2003-06-05 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
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WO2003045942A2 (en) * 1998-09-04 2003-06-05 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
WO2000069432A1 (en) * 1999-05-18 2000-11-23 Teijin Limited Remedies or preventives for diseases in association with chemokines
WO2006137350A1 (en) * 2005-06-22 2006-12-28 Kissei Pharmaceutical Co., Ltd. Novel furopyridine derivative, pharmaceutical composition comprising the derivative, and use of the derivative or composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8550346B2 (en) 2010-09-29 2013-10-08 Beijing Mechanical Equipment Institute Low-altitude low-speed small target intercepting method

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