WO2003091209A1 - Procédé de production d'un composé de 1-(alkyle inférieur)-3-hydroxypyrrolidine - Google Patents

Procédé de production d'un composé de 1-(alkyle inférieur)-3-hydroxypyrrolidine Download PDF

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Publication number
WO2003091209A1
WO2003091209A1 PCT/JP2003/004582 JP0304582W WO03091209A1 WO 2003091209 A1 WO2003091209 A1 WO 2003091209A1 JP 0304582 W JP0304582 W JP 0304582W WO 03091209 A1 WO03091209 A1 WO 03091209A1
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WO
WIPO (PCT)
Prior art keywords
salt
hydroxypyrrolidine
general formula
lower alkyl
hydroxyl group
Prior art date
Application number
PCT/JP2003/004582
Other languages
English (en)
Japanese (ja)
Inventor
Fumihiko Kano
Natsuki Mori
Original Assignee
Kaneka Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kaneka Corporation filed Critical Kaneka Corporation
Priority to AU2003236065A priority Critical patent/AU2003236065A1/en
Publication of WO2003091209A1 publication Critical patent/WO2003091209A1/fr

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Classifications

    • 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
    • C07D207/12—Oxygen or sulfur atoms

Definitions

  • the present invention is useful as an intermediate for synthesizing fine chemicals such as pharmaceuticals and agricultural chemicals.
  • X represents a hydroxyl group or a protected hydroxyl group
  • R 1 and R 2 each independently represent a hydrogen atom or a lower alkyl group.
  • the present invention relates to a method for producing a salt.
  • R ′ and R 2 each independently represent a hydrogen atom or a lower alkyl group
  • 3-hydroxypyrrolidine is reacted with benzaldehyde in the presence of a metal catalyst in a catalytic reduction reaction to produce 1-benzyl-3-hydroxypyrrolidine (Japanese Patent Application Laid-Open No. H11-212,469).
  • the present invention is based on 1-benzyl-3-hydroxypyrrolidines or 3-hydroxypyrrolidines as a raw material, in an inexpensive and simple manner, with good selectivity (less by-products of quaternary ammonium salts). It is an object of the present invention to provide a method for producing a lower alkyl-3-hydroxypyrrolidine.
  • the catalytic reduction reaction is used to convert a 1-benzyl-3-hydroxypyrrolidine represented by the general formula (2) or a salt thereof to a 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof.
  • the conversion of 3-hydroxypyrrolidines or a salt thereof to a 1-lower alkyl-3-hydroxypyrrolidine represented by the general formula (1) or a salt thereof is carried out by a 3-hydroxypyrrolidine (3) or They have found that they can be performed continuously or simultaneously without isolating the salt, and have completed the present invention.
  • the present invention relates to the general formula (1)
  • X represents a hydroxyl group or a protected hydroxyl group
  • R 1 and R 2 each independently represent a hydrogen atom or a lower alkyl group.
  • the present invention provides a method of reacting a 3-hydroxypyrrolidine represented by the general formula (3) or a salt thereof with an aldehyde or ketone represented by the general formula (4) to thereby represent the compound represented by the general formula (1).
  • the 1-benzyl-3-hydroxypiperidines represented by the general formula (2) used in the present invention can be used for reducing 1-benzyl-3-pyrrolidinone described in Japanese Patent Application Laid-Open No. H10-150997 to reduce microorganisms.
  • the 1-benzyl-3-hydroxypyrrolidine obtained by the above method can be prepared by protecting a hydroxyl group as required.
  • the 3-hydroxypyrrolidine represented by the general formula (3) is obtained by converting 1-benzyl-3-hydroxypyrrolidine (2) obtained as described above to It can be prepared by a method of hydrocracking using a noble metal catalyst described in 2 etc.
  • X represents a hydroxyl group or a protected hydroxyl group.
  • the protective group for the hydroxyl group is not particularly limited, and ether-based protective groups such as methoxymethyl ether, benzyl ether, tetrahydropyranyl ether, and trimethylsilyl ether, acetyl ester, benzoyl ester, methanesulfonyl ester, and methyl carbonate Examples include ester-based protecting groups such as esters.
  • the 1-benzyl-3-hydroxypyrrolidine represented by the general formula (2) and the 3-hydroxypyrrolidine represented by the general formula (3) may be used as a free form, or may be used as an acid.
  • the salt form thereof can also be suitably used in the present invention.
  • the acid that forms the salt is not particularly limited, but mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; carboxylic acids such as formic acid, acetic acid, oxalic acid, maleic acid, phthalic acid, and tartaric acid; Organic sulfonic acids such as methanesulfonic acid and toluenesulfonic acid; organic phosphonic acids such as methanephosphonic acid and benzoic acid; and amino acids such as glycine, alanine and aspartic acid. be able to.
  • the salt of 1-benzyl-3-hydroxypyrrolidine (2) with an acid and the salt of 3-hydroxypyrrolidine (3) with an acid may be prepared in advance in the form of a salt. Before or after the start of the catalytic reduction reaction of the present invention, it may be formed in a reaction system by mixing with the above acid.
  • lower alkylation is performed using an aldehyde or ketone represented by the general formula (4).
  • R 1 and R 2 independently represent a hydrogen atom or a lower alkyl group.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms.
  • the linear alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group.
  • the branched alkyl group having 1 to 4 carbon atoms include an isopropyl group, a sec-butyl group, and a t-butyl group.
  • aldehyde or ketone represented by the general formula (4) include, for example, formaldehyde, paraformaldehyde, acetaldehyde, propionylaldehyde, butyraldehyde, pentylaldehyde, acetone, 2-butanone, 2-pentanol Non-, 3-pentanone, 2-hexanone, 3-hexanone, 3-heptanone, -heptanone, methyl isopropyl ketone, X-isopropylisopropyl ketone, disopropyl ketone, methyl-t-butyl ketone, Ethyl t-butyl ketone and the like. From the viewpoint of the reactivity with 3-hydroxypyrrolidines and the usefulness of the product, preferred is formaldehyde, acetoaldehyde or acetone.
  • the starting material 1-benzyl-3-hydroxypyrrolidine or a salt thereof
  • the aldehyde or ketone is mixed with the system, followed by contact.
  • debenzylation and lower alkylation are successively performed to produce 1-lower alkyl-3-hydroxypyrrolidine or a salt thereof.
  • continuous means that lower alkylation is continuously performed in the same reaction solution without isolating 3-hydroxypyrrolidine or a salt thereof produced by the debenzylation reaction. Therefore, the method may not include a step of isolating 3-hydroxypyrrolidine or a salt thereof.
  • the method may not include a step of isolating 3-hydroxypyrrolidine or a salt thereof.
  • This method is usually performed using a solvent.
  • the solvent those used in ordinary catalytic reduction reactions can be used.
  • examples include alcohols such as methanol and ethanol, carboxylic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, toluene and hexane. Hydrocarbons, amides such as dimethylformamide, and water.
  • These solvents may be used alone or in combination of two or more.
  • the amount of the solvent to be used is not particularly limited, and may be appropriately set in consideration of economy. Usually, the amount of the solvent is about 0.1 to 1 times the weight of the raw material 1-benzyl-3-hydroxypyrrolidine. Use 0 times the weight Good results are obtained.
  • the amount of the aldehyde or ketone used is not particularly limited as long as it is 1 equivalent or more based on the starting material, 1-benzyl-13-hydroxypyrrolidine or a salt thereof, and the aldehyde or ketone is used as a reaction solvent. Can also be used.
  • metal catalyst those known as catalysts used in the catalytic reduction reaction can be used, and examples thereof include palladium-based catalysts, platinum-based catalysts, rhodium-based catalysts, ruthenium-based catalysts, and nickel-based catalysts. It may be supported on silica or silica. For example, a palladium catalyst (palladium carbon) supported on charcoal powder, Raney nickel catalyst and the like can be mentioned. These metal catalysts can be used alone or in combination of two or more. In particular, when debenzylation and lower alkylation are carried out at the same time, if one of the metal catalysts is a palladium-based catalyst, good results can be obtained from the viewpoint of the reaction rates of debenzylation and lower alkylation. Therefore, it is preferable to use palladium carbon or the like.
  • the amount of the catalyst used is not particularly limited, but by using 0.1 to 20% by weight based on 1-benzyl-1-hydroxypyrrolidine or its salt as a raw material, the reaction can be performed with high selectivity. , And can be implemented efficiently.
  • the metal catalyst used in the debenzylation can be used as it is for the lower alkylation without any additional metal catalyst.
  • the catalytic reduction reaction is preferably performed under a hydrogen atmosphere at normal pressure (about 0.1 IMPa) to 1 MPa, more preferably at normal pressure (about 0.1 MPa) to 5 MPa, preferably a reaction solution.
  • normal pressure about 0.1 IMPa
  • 5 MPa normal pressure
  • 1-benzyl-3-hydroxypyrrolidine or a salt thereof can be used as a starting material without isolating the 3-hydroxypyrrolidine (3) or a salt thereof after debenzylation, to obtain a 1-lower alkyl radical.
  • 3-hydroxypyrrolidine (1) or a salt thereof can be produced.
  • 3-hydroxypyrrolidines (3) or salts thereof which have been previously debenzylated are catalytically reduced with the above aldehyde or ketone in the presence of a metal catalyst to obtain 1-lower alkyl-1-hydroxypyrrolidine.
  • Production of class (1) or a salt thereof can also be suitably carried out.
  • the method of the present invention can be applied to optically active 3-hydroxypyrrolidines or salts thereof, and 1-benzyl-3-hydroxypyrrolidines or salts thereof.
  • Optically active monoalkyl-1-hydroxypyrrolidines or salts thereof having the same configuration as the raw materials can be obtained.
  • the 1-lower alkyl-13-hydroxypyrrolidines or salts thereof produced by the above method can be easily isolated by post-treatment such as filtration of the catalyst, followed by concentration, distillation and the like.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne un procédé permettant de produire facilement, à faible coût, et avec une sélectivité satisfaisante, une 1-(alkyle inférieur)-3-hydroxypyrrolidine convenant comme intermédiaire pour des produits de chimie fine tels que des médicaments et des produits chimiques pour l'agriculture. En l'occurrence, on prend un composé, soit de 1-benzyl-3-hydroxypyrrolidine, soit de 3-hydroxypyrrolidine, et on le réduit cataytiquement avec un aldéhyde ou un cétone en présence d'un métal catalyseur. On arrive ainsi à produire ce composé de 1-(alkyle inférieur)-3-hydroxypyrrolidine.
PCT/JP2003/004582 2002-04-23 2003-04-10 Procédé de production d'un composé de 1-(alkyle inférieur)-3-hydroxypyrrolidine WO2003091209A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003236065A AU2003236065A1 (en) 2002-04-23 2003-04-10 Process for producing 1-(lower alkyl)-3-hydroxypyrrolidine compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002120782 2002-04-23
JP2002-120782 2002-04-23

Publications (1)

Publication Number Publication Date
WO2003091209A1 true WO2003091209A1 (fr) 2003-11-06

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PCT/JP2003/004582 WO2003091209A1 (fr) 2002-04-23 2003-04-10 Procédé de production d'un composé de 1-(alkyle inférieur)-3-hydroxypyrrolidine

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AU (1) AU2003236065A1 (fr)
WO (1) WO2003091209A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017138588A1 (fr) 2016-02-10 2017-08-17 住友化学株式会社 Procédé de production de 1-méthylpyrrolidin-3-ol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63122658A (ja) * 1986-10-27 1988-05-26 エイ・エッチ・ロビンス・カンパニー・インコーポレーテッド ３ーピロリジノール類の製法
JPH01207266A (ja) * 1988-02-13 1989-08-21 Denki Kagaku Kogyo Kk ３−ヒドロキシピロリジンまたはその誘導体の製造法
JPH02212469A (ja) * 1989-02-10 1990-08-23 Kanegafuchi Chem Ind Co Ltd Ｎ―ベンジルピロリジン誘導体又はその塩の製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63122658A (ja) * 1986-10-27 1988-05-26 エイ・エッチ・ロビンス・カンパニー・インコーポレーテッド ３ーピロリジノール類の製法
JPH01207266A (ja) * 1988-02-13 1989-08-21 Denki Kagaku Kogyo Kk ３−ヒドロキシピロリジンまたはその誘導体の製造法
JPH02212469A (ja) * 1989-02-10 1990-08-23 Kanegafuchi Chem Ind Co Ltd Ｎ―ベンジルピロリジン誘導体又はその塩の製造方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017138588A1 (fr) 2016-02-10 2017-08-17 住友化学株式会社 Procédé de production de 1-méthylpyrrolidin-3-ol
CN108698989A (zh) * 2016-02-10 2018-10-23 住友化学株式会社 用于制备1-甲基吡咯烷-3-醇的方法
CN108698989B (zh) * 2016-02-10 2021-05-11 住友化学株式会社 用于制备1-甲基吡咯烷-3-醇的方法
US11084787B2 (en) 2016-02-10 2021-08-10 Sumitomo Chemical Company Limited Method for producing 1-methylpyrrolidin-3-ol

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Publication number Publication date
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