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WO2007024113A1 - Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée - Google Patents

Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée Download PDF

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Publication number
WO2007024113A1
WO2007024113A1 PCT/KR2006/003341 KR2006003341W WO2007024113A1 WO 2007024113 A1 WO2007024113 A1 WO 2007024113A1 KR 2006003341 W KR2006003341 W KR 2006003341W WO 2007024113 A1 WO2007024113 A1 WO 2007024113A1
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Prior art keywords
hydroxy
chiral
group
compound
set forth
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English (en)
Inventor
Chung-Woo Lim
Chang Jin Boo
Ki Hyun Kim
Seong-Jin Kim
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RSTECH Corp
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RSTECH Corp
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Priority to EP06783728A priority Critical patent/EP1926709A4/fr
Priority to JP2008527850A priority patent/JP2009507783A/ja
Priority claimed from KR1020060080184A external-priority patent/KR100743617B1/ko
Publication of WO2007024113A1 publication Critical patent/WO2007024113A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D207/12—Oxygen or sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of a chiral
  • the present invention relates to an efficient process for the preparation of optically pure chiral 3-hydroxypyrrolidine compound and derivatives thereof, comprised of introducing a suitable protecting group to the starting material 3-chloro-2-hydroxypropionitrile in order to prevent formation of side products during reduction of the nitrile group of the starting material and in-situ intramolecular cyclization at a hydrogenation reaction.
  • Chiral 3-hydroxypyrrolidine and derivatives thereof are essential intermediates of a variety of chiral medicines, including antibiotics, analgesics, thrombolytic drugs, antipsychotics, etc.
  • Various drugs derived from 3-hydroxypyrrolidine and derivatives thereof are commercially available.
  • Several compounds are also reported to be clinically tested. Therefore, it is expected that the demand on chiral 3-hydroxypyrrolidine and its derivatives increases more and more. For these reasons, researches on the inexpensive and efficient production of chiral 3-hydroxypyrrolidine and derivatives thereof take an important role in the field of medicine industry.
  • chiral 3-hydroxypyrrolidine derivative was also prepared from decarbonation of chiral 4-hydroxy-2-pyrrolidinecarboxylic acid through combinational treatment with 2-cyclohexen-l-one and cyclohexanol [WO 91/09013; U.S. Patent No. 5,233,053; Chem. Lett., 1986, 893].
  • this process is complicated and exhibits a low yield, making it inappropriate for industrial- scale production.
  • 3-hydroxypyrrolidine compound represented by formula 1 is prepared from the following reactions: protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile represented by formula 2, hydrogenation of the obtained product, optional N-derivatization, and deprotection.
  • the protection of the hydroxyl group of the chiral 3-chloro-2-hydroxypropionitrile can minimize side reactions during the hydrogenation and increases the total yield.
  • the targeted compound is prepared in high optical purity. Further, the protection of the hydroxyl group effectively prevents the competitive derivatization by the oxygen atom of the hydroxyl group.
  • the intermediate compounds from the chiral 3-chloro-2-hydroxypropionitrile can be subject as a crude product, without any particular purification, to the subsequent reactions such as hydroxy protection, hydrogenation, optional derivatization and deprotection, This simplifies the reaction process and improves the production yield. Accordingly, the process of the present invention makes it possible to produce the 3-hydroxypyrrolidine compound represented by formula 1, which is an essential intermediate for a variety of chiral medicines, in an effective manner and in an industrial scale. Best Mode for Carrying Out the Invention
  • the process in accordance with the present invention comprises the steps of (a) protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a hydroxy-protecting group, (b) subjecting the obtained hydroxy-protected compound to a hydrogenation reaction to obtain a corresponding hydroxy-protected pyrrolidine compound or hydrochloride salt thereof and (c) if necessary, deprotecting the hydroxy-protected pyrrolidine compound, or N - derivatizing the hydroxy-protected pyrrolidine compound by reacting the hydroxy- protected pyrrolidine compound with a substrate susceptible to a nucleophilic attack and then deprotecting the obtained N-derivatized pyrrolidine compound.
  • the process in accordance with the present invention is summarized in the following scheme 1 :
  • the targeted chiral 3-hydroxypyrrolidine compound can be prepared in high yield and with high optical purity, through subsequent reactions: protection of the hydroxy group; reduction of the nitrile group and in situ intramolecular cyclization by hydrogenation; optional JV-derivatization and/or de- protection of the hydroxyl protecting group.
  • the reduction of the nitrile group is one of effective organic synthesis techniques to prepare a primary amine and is a commercially available process [The Chemistry of the Cyano Group, John Wiley and Sons, 1970, Chapter 7; U.S. Patent No. 5,237,088; U.S. Patent No. 5,801,286; U.S. Patent No. 5,777,166].
  • the reduction of the nitrile group were carried out in a presence of various reducing agents, for example, metal hydrides such as lithium aluminum hydride or sodium borohydride, optionally in combination with an additive [Chem. Soc.
  • the primary amine compound can be prepared by reducing the nitrile group through hydrogenation in a presence of a metal catalyst such as palladium, platinum, Raney nickel, Raney cobalt, etc. This process is advantageous in that the product can be easily obtained by filtering out the catalyst and removing the solvent.
  • a metal catalyst such as palladium, platinum, Raney nickel, Raney cobalt, etc.
  • 3-hydroxypyrrolidine could not be obtainable in high yield and with high purity from direct hydrogenation of the chiral 3-chloro-2-hydroxypropionitrile of formula 2 due to the formation of various side products. Moreover, since the side reactions were reinforced in a large-scale preparation, new solution to avoid the problems should be investigated.
  • the production yield of hydrogenation and subsequent deprotection in a situation that an alkyl group such as methyl or tetrahydropyran was introduced, as a protecting group, to protect the hydroxy group of the compound the formula 2, was found to be as low as 30 %.
  • hydroxy-protecting group is a silyl group.
  • the chiral 3-chloro-2-hydroxypropionitrile having formula 2 is firstly reacted with a silylizing agent to accomplish the protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile with a silyl group.
  • a silylizing agent is firstly reacted with a silylizing agent to accomplish the protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile with a silyl group.
  • R', R" and R'" represent substituents.
  • R', R" and R'" are, each independently, C -C alkyl, C -C cycloalkyl, C -C alkene, C -C alkyne, C -C alkoxy, C -C aryl or (CH ) -R (wherein R is C -C cycloalkyl, C -C alkene, C -C alkyne, C
  • the silyl group, introduced as a hydroxyl protecting group, is very stable under various chemical reaction conditions, excluding an acidic condition.
  • the introduction and deprotection of the silyl group can be easily carried out [Protecting Groups, Thieme Medical Publishers Inc,. New York, 1994; Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991].
  • the protection of the hydroxy group with the silyl group can be easily achieved by reacting a chiral 3-chloro-2-hydroxypropionitrile compound of formula 2 with a silylizing agent in a presence of a base.
  • the silylizing agent that can be represented by R'R"R'"Si-Y (wherein, R', R" and R'" are the same as defined in the above and Y represents a leaving group such as halide or sulfonate) is added in an amount of 0.8 - 5 equivalents, preferably in an amount of 1.0 - 2 equivalents, based on the chiral 3-chloro-2-hydroxypropionitrile of formula 2.
  • a base imidazole, 2,6-lutidine, N,N - dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof can be mentioned.
  • Preferable is trialkylamine.
  • aromatic organic solvents such as toluene and benzene, halogenated alkane such as dichloromethane and chloroform and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used.
  • Reaction temperature is preferably in the range of 0 to 100 0 C, more preferably of 10 to 4O 0 C.
  • Another preferable hydroxy-protecting group is a benzyl group.
  • the benzyl group is known to be deproteced during the hydrogenation reaction. Nonetheless, the benzyl group, introduced as a hydroxy-protecting group of the chiral 3-chloro-2-hydroxypropionitrile, is stable under the hydrogenation using Raney nickel and provides satisfactory results.
  • a metal catalyst such as palladium and platinum, the benzyl group was deprotected during the hydrogenation and showed very low yield.
  • * represents a chiral center and Z means a hydroxy-protecting group, preferably a silyl group.
  • the hydrogenation is performed in a presence of a metal catalyst and under hydrogen atmosphere.
  • the metal catalyst that can be used in the hydrogenation is not particularly limited and may be any one generally known in the art. Preferable is palladium (Pd), platinum (Pt), Raney nickel (Raney-Ni) and Raney cobalt (Raney-Co). In a case that the benzyl group is used as the hydroxy-protecting group, Raney nickel (Raney-Ni) is preferable.
  • the metal catalyst is added in an amount of 5 - 80 wt%, preferably in an amount of 5 - 25 wt%.
  • the hydrogen gas is supplied in a pressure of 1 - 50 bar, preferably 2-10 bar.
  • the reaction is performed at a temperature of 25 - 200 0 C, preferably 50 - 15O 0 C under stirring for 1 - 30 hours, preferably 2 - 5 hours. After all the reactants were consumed, typical filtration and distillation under reduced pressure gave a hydroxy-protected pyrrolidine compound or hydrochloride salt thereof, which is represented by formula 4.
  • the solvent to be used is not particularly limited and may be any one commonly used in the art. Specifically, JV,./V-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used.
  • the alcohol include C 1 -C 4 alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
  • C 1 -C 4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol.
  • the hydrochloride salt of the hydroxy-protected pyrrolidine was treated with an inorganic base (e.g., NaOH) to obtain a free base.
  • an inorganic base e.g., NaOH
  • the compound represented by the formula 4 can be directly applicable to the deprotection or the N-derivatization in the form of hydrochloride salt, because deprotection is not affected by the presence of HCl.
  • N-derivatization is affected by the presence of HCl, because the ⁇ -derivatization is normally performed in a presence of excess base.
  • the pyrrolidine compound of formula 4 can be used in the deprotection and the N-derivatization in a form of the hydrochloride salt.
  • the resultant hydroxy-protected pyrrolidine compound or its hydrochloride salt represented by formula 4 is converted to the chiral 3-hydroxypyrrolidine or derivatives thereof through optional N-derivatization and deprotection.
  • the targeted chiral 3-hydroxypyrrolidine or N-substituted chiral 3-hydroxypyrrolidine having formula 1 is prepared from the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt.
  • Deprotection under the acidic condition gives chiral 3-hydroxypyrrolidine as an acid additive salt, from which the chiral 3-hydroxypyrrolidine can be easily recovered during a workup process by the treatment with a base (e.g., an inorganic base containing hydroxy, phosphate or carbonate group).
  • a base e.g., an inorganic base containing hydroxy, phosphate or carbonate group.
  • Deprotection of the benzyl group is accomplishable through hydrogenation in a presence of a metal catalyst such as palladium and platinum.
  • a metal catalyst such as palladium and platinum.
  • the targeted pyrrolidine compound is a benzyl-protected compound, deprotection would be unnecessary.
  • Specific conditions for the de- protection of the silyl group are as follows.
  • the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is firstly dissolved into an organic solvent and a deprotecting agent is added, under stirring, to the solution in an amount of 0.1 - 10 equivalents (preferably in 0.5 - 2.0 equivalents) at a reaction temperature of 0 - 100 0 C (preferably 10 - 3O 0 C).
  • the solvent is not particularly limited and may be anyone commonly used in the art. Specifically, ⁇ f, ⁇ f-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used.
  • the hydroxy-protected pyrrolidine compound of formula 4 is sequentially subject to JV-derivatization and deprotection to provide chiral JV-substituted 3-hydroxypyrrolidine compound.
  • the JV-derivatization is performed by reacting the hydroxy-protected pyrrolidine compound of formula 4 with a substrate susceptible to a nucleophilic attack. That is, the ./V-derivatization is carried out by nucleophilic attack of the nitrogen atom of the hydroxy-protected pyrrolidine compound of formula 4 to the substrate susceptible to the nucleophilic attack.
  • the substrate susceptible to the nucleophilic attack is typically represented by the formula R-Y (wherein R is car- bohydride and Y is a leaving group).
  • R is car- bohydride and Y is a leaving group.
  • the leaving group include a halogen atom, sulfonate and anhydride.
  • the substrate is normally added in an amount of 0.8 - 2 equivalents, preferably in an amount of 1.0 - 2.0 equivalents.
  • the N - derivatization is performed in a presence of a base.
  • the base include imidazole, 2,6-lutidine, JV,./V-dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof.
  • Preferable is trialkylamine.
  • trialkylamine examples include trimethylamine, triethylamine and diisopropylethylamine.
  • the base is added in an amount of 0.8 - 10 equivalents, preferably in an amount of 1.0 - 3.0 equivalents, based on the hydroxy-protected pyrrolidine compound of formula 4.
  • the organic solvent used in the reaction is not particularly limited and may be anyone commonly used in the art. Examples of the organic solvent include JV,./V-dimethylformamide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon and ether.
  • aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform or ethers such as ethyl ether, tetrahydrofuran and dioxane may be used.
  • Reaction temperature can be suitably adjustable depending on the substrate to be used, which is well known to the person of ordinary skill in the art. Typically, the reaction is carried out at a temperature of 0 - 100 0 C.
  • the targeted compound is obtainable in high purity after typical workup process.
  • the resulting compound can be applicable to the next deprotection without any further special purification (e.g., fractional distillation and recrystallization). This contributes to the simplification of the process and the improvement of production yield.
  • the deprotection process can be carried out in the same manner as described in the above. After de- protection of the hydroxy-protecting group, the targeted chiral JV-substituted 3-hydroxypyrrolidine compound is finally prepared.
  • the chiral 3-hydroxypyrrolidine may directly undergo N - derivatization by the reaction with a substrate susceptible to nucleophilic attack and the obtained compound is used as an intermediate in the synthesis of chiral medicines.
  • direct derivatization of the chiral 3-hydroxypyrrolidine compound involves competitive derivatization by the nitrogen atom and the oxygen atom of the chiral 3-hydroxypyrrolidine.
  • both the nitrogen atom and the oxygen atom competitively participate in the derivatization reaction.
  • the competitive nucleophilic attack by the oxygen atom produces adverse side product, which reduces the production yield of the target compound and makes the purification process complicated.
  • 3-hydroxypyrrolidine compound represented by the following formula 1 can be prepared:
  • Z represents hydrogen or benzyl and R is hydrogen, C -C alkyl
  • C cycloalkyl, C -C cycloalkenyl, heterocycle or polycycle C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, r phos ⁇ phonate, ' X p-hos I p-hine,' sulfony J l or ( y CH 2 ) k -R 3 (wherein R 3 is C 2 -C 10 alkene, C 2 -C 10 alkyne, C -C alkoxy, C -C aryl, C -C cycloalkyl, C -C cycloalkenyl, heterocycle
  • Example 4 (66.9 mmol) obtained from Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred under 20 bar of hydrogen pressure while varying the reaction temperatures of 3O 0 C to 12O 0 C.
  • the target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.
  • Example 4 (66.9 mmol) obtained in Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred at 5O 0 C, 7O 0 C and 100 0 C, respectively, while varying the hydrogen pressure.
  • the target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.
  • Example 10 Preparation of (R )- N -benzyl-3-hydroxypyrrolidine [91] To 2 L high-pressure reactor, 100 g of (R)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile dissolved into methanol (500 mL) and 25 g of Raney-Ni suspended in methanol (500 mL) were added. The mixture was heated to 100 0 C and stirred for 2 hours under 5 bar of hydrogen pressure. The reaction solution was cooled to room temperature and filtered through celite to remove the catalyst. 34.2 g of NaOH and 65.0 g of benzyl chloride were successively added dropwise to the remaining filtrate.
  • the obtained filtrate was concentrated under reduced pressure to obtain 98.0 g of the targeted compound (R)-3-(benzyloxy)-4-chlorobutanenitrile (yield: 93 %).
  • the obtained product was subject to the subsequent hydrogenation without any further purification.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé efficace de synthèse de 3-hydroxypyrrolidine chirale optiquement pure ou de dérivés de ce composé. Plus particulièrement, la présente invention concerne un procédé efficace de synthèse de 3-hydroxypyrrolidine chirale ou de dérivés de ce composé, constitué de l'introduction d'un groupement protecteur adapté au niveau du produit de départ, le 4-chloro-3-hydroxybutyronitrile. L'introduction du groupement protecteur de fonction hydroxy confère des avantages : inhibition efficace de la formation de sous-produits, performance améliorée de la réduction du groupement nitrile du produit de départ, et performance améliorée de la cyclisation intramoléculaire in situ. Le composé de type 3-hydroxypyrrolidine chirale est obtenu avec un rendement élevé et une pureté élevée.
PCT/KR2006/003341 2005-08-25 2006-08-24 Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée Ceased WO2007024113A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP06783728A EP1926709A4 (fr) 2005-08-25 2006-08-24 Procédé de synthèse d'un composé chiral de type 3-hydroxypyrrolidine et de dérivés dudit composé de pureté optique élevée
JP2008527850A JP2009507783A (ja) 2005-08-25 2006-08-24 高光学純度を有するキラル３−ヒドロキシピロリジン化合物及びその誘導体の製造方法

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KR10-2005-0078199 2005-08-25
KR20050078199 2005-08-25
KR10-2006-0080184 2006-08-24
KR1020060080184A KR100743617B1 (ko) 2005-08-25 2006-08-24 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058429A1 (fr) 2008-11-24 2010-05-27 Council Of Scientific & Industrial Research Procédé de préparation de n-benzyl-3-hydroxypyrrolidines optiquement actives
CN111518015A (zh) * 2020-05-20 2020-08-11 上海合全药物研发有限公司 一种叔丁基-8-氧亚基-2-氮杂螺[4.5]癸烷-2-甲酸基酯的制备方法
CN111763228A (zh) * 2020-08-03 2020-10-13 连云港宏业化工有限公司 （3s）-4-氯-3-[（三甲基甲硅烷基）氧基]丁腈合成方法
WO2025087822A1 (fr) 2023-10-23 2025-05-01 F. Hoffmann-La Roche Ag Nouveau procédé de préparation de chlorhydrate de (3r)-fluoropyrrolidine

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3823187A (en) 1972-06-19 1974-07-09 Bristol Myers Co Production of l(-)-gamma-amino-alpha-hydroxybutyric acid
JPS6163652A (ja) 1984-09-04 1986-04-01 Yamanouchi Pharmaceut Co Ltd （ｓ）−（−）−１−ベンジル−３−ヒドロキシピロリジンの製造法
EP0269258A2 (fr) 1986-10-27 1988-06-01 A.H. Robins Company, Incorporated Procédé de préparation d'un composé pyrrolidinol
JPH01141600A (ja) 1987-11-28 1989-06-02 Kanegafuchi Chem Ind Co Ltd 光学活性３−ヒドロキシピロリジン誘導体の製造法
EP0347818A2 (fr) 1988-06-22 1989-12-27 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé de préparation du 3-pyrrolidinol
EP0431521A1 (fr) 1989-12-02 1991-06-12 Kanegafuchi Chemical Industry Co., Ltd. Dérivés d'aminobutanol et procédé pour la préparation de 3-pyrrolidinol à partir de ceux-ci
WO1991009013A1 (fr) 1989-12-12 1991-06-27 Pfizer Limited Antagonistes de recepteurs muscariniques
EP0452143A2 (fr) 1990-04-11 1991-10-16 Takasago International Corporation Procédé pour la préparation de dérivés optiquement actifs de 3-hydroxypyrrolidine
JPH04131093A (ja) 1990-09-19 1992-05-01 Denki Kagaku Kogyo Kk 混合物の製造法
US5233053A (en) 1989-03-17 1993-08-03 Pfizer Inc. Pyrrolidine derivatives
US5237088A (en) 1992-03-25 1993-08-17 E. I. Du Pont De Nemours And Company Transfer hydrogenation of nitriles using amine donors
JPH0673000A (ja) 1992-08-28 1994-03-15 Daicel Chem Ind Ltd 光学異性体の分離法
JPH06141876A (ja) 1992-11-10 1994-05-24 Kyowa Hakko Kogyo Co Ltd 光学活性なｎ−ベンジル−３−ピロリジノールの製造法
JPH06211782A (ja) 1993-01-19 1994-08-02 Denki Kagaku Kogyo Kk アルコールとその誘導体の分離法
WO1995003421A1 (fr) 1993-07-19 1995-02-02 Dsm N.V. Procede de production enzymatique de 3-pyrrolidinol n-substitue optiquement actif
JPH07116138A (ja) 1993-10-26 1995-05-09 Matsushita Electric Works Ltd 脈拍検出方法及びその装置
US5801286A (en) 1993-12-28 1998-09-01 Rhone-Poulenc Chimie Process for the preparation of a catalyst for the hydrogenation of nitriles to amines and use of this catalyst in hydrogenation
US20020106763A1 (en) * 1998-11-17 2002-08-08 Zhi Li Process for preparing optically active 3-hydroxy-pyrrolidine derivatives by enzymatic hydroxylation
WO2003097594A1 (fr) * 2002-05-20 2003-11-27 Samsung Fine Chemicals Co., Ltd. Procede de preparation d'une 3-hydroxy-pyrrolidine optiquement pure
KR20040058612A (ko) * 2002-12-27 2004-07-05 한국화학연구원 4-히드록시-2-피롤리디논의 제조방법
WO2005115978A1 (fr) * 2004-05-25 2005-12-08 Ahn-Gook Pharmaceutical Co., Ltd. Procede de preparation d'acetamide de 4-hydroxy-2-oxo-1-pyrrolidine optiquement pur

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3823187A (en) 1972-06-19 1974-07-09 Bristol Myers Co Production of l(-)-gamma-amino-alpha-hydroxybutyric acid
JPS6163652A (ja) 1984-09-04 1986-04-01 Yamanouchi Pharmaceut Co Ltd （ｓ）−（−）−１−ベンジル−３−ヒドロキシピロリジンの製造法
EP0269258A2 (fr) 1986-10-27 1988-06-01 A.H. Robins Company, Incorporated Procédé de préparation d'un composé pyrrolidinol
JPH01141600A (ja) 1987-11-28 1989-06-02 Kanegafuchi Chem Ind Co Ltd 光学活性３−ヒドロキシピロリジン誘導体の製造法
EP0347818A2 (fr) 1988-06-22 1989-12-27 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé de préparation du 3-pyrrolidinol
EP0347818B1 (fr) * 1988-06-22 1995-08-23 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Procédé de préparation du 3-pyrrolidinol
US5233053A (en) 1989-03-17 1993-08-03 Pfizer Inc. Pyrrolidine derivatives
EP0431521A1 (fr) 1989-12-02 1991-06-12 Kanegafuchi Chemical Industry Co., Ltd. Dérivés d'aminobutanol et procédé pour la préparation de 3-pyrrolidinol à partir de ceux-ci
WO1991009013A1 (fr) 1989-12-12 1991-06-27 Pfizer Limited Antagonistes de recepteurs muscariniques
US5144042A (en) 1990-04-11 1992-09-01 Takasago International Corporation Process for preparing optically active 3-hydroxypyrrolidine derivatives
EP0452143A2 (fr) 1990-04-11 1991-10-16 Takasago International Corporation Procédé pour la préparation de dérivés optiquement actifs de 3-hydroxypyrrolidine
JPH04131093A (ja) 1990-09-19 1992-05-01 Denki Kagaku Kogyo Kk 混合物の製造法
US5237088A (en) 1992-03-25 1993-08-17 E. I. Du Pont De Nemours And Company Transfer hydrogenation of nitriles using amine donors
JPH0673000A (ja) 1992-08-28 1994-03-15 Daicel Chem Ind Ltd 光学異性体の分離法
JPH06141876A (ja) 1992-11-10 1994-05-24 Kyowa Hakko Kogyo Co Ltd 光学活性なｎ−ベンジル−３−ピロリジノールの製造法
JPH06211782A (ja) 1993-01-19 1994-08-02 Denki Kagaku Kogyo Kk アルコールとその誘導体の分離法
WO1995003421A1 (fr) 1993-07-19 1995-02-02 Dsm N.V. Procede de production enzymatique de 3-pyrrolidinol n-substitue optiquement actif
JPH07116138A (ja) 1993-10-26 1995-05-09 Matsushita Electric Works Ltd 脈拍検出方法及びその装置
US5801286A (en) 1993-12-28 1998-09-01 Rhone-Poulenc Chimie Process for the preparation of a catalyst for the hydrogenation of nitriles to amines and use of this catalyst in hydrogenation
US20020106763A1 (en) * 1998-11-17 2002-08-08 Zhi Li Process for preparing optically active 3-hydroxy-pyrrolidine derivatives by enzymatic hydroxylation
WO2003097594A1 (fr) * 2002-05-20 2003-11-27 Samsung Fine Chemicals Co., Ltd. Procede de preparation d'une 3-hydroxy-pyrrolidine optiquement pure
KR20040058612A (ko) * 2002-12-27 2004-07-05 한국화학연구원 4-히드록시-2-피롤리디논의 제조방법
WO2005115978A1 (fr) * 2004-05-25 2005-12-08 Ahn-Gook Pharmaceutical Co., Ltd. Procede de preparation d'acetamide de 4-hydroxy-2-oxo-1-pyrrolidine optiquement pur

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Protecting Groups", 1994, THIEME MEDICAL PUBLISHERS INC, pages: 28
"Protective Groups in Organic Synthesis", 1991, JOHN WILEY AND SONS, INC
"Reduction in organic chemistry", 1984, ELLIS HORWOOD LIMITED, pages: 173
BULL CHEM. SOC, JPN., vol. 69, 1996, pages 207
CHEM. LETT., 1986, pages 893
J. MED. PHARM. CHEM., vol. 1, 1959, pages 76
See also references of EP1926709A4 *
SYNTH. COMMUN., vol. 13, 1983, pages 117
SYNTH. COMMUN., vol. 15, 1985, pages 587
SYNTH. COMMUN., vol. 16, 1986, pages 1815

Cited By (5)

* Cited by examiner, † Cited by third party
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WO2010058429A1 (fr) 2008-11-24 2010-05-27 Council Of Scientific & Industrial Research Procédé de préparation de n-benzyl-3-hydroxypyrrolidines optiquement actives
US8445700B2 (en) 2008-11-24 2013-05-21 Council Of Scientific & Industrial Research Process for the preparation of optically active N-benzyl-3 hydroxypyrrolidines
CN111518015A (zh) * 2020-05-20 2020-08-11 上海合全药物研发有限公司 一种叔丁基-8-氧亚基-2-氮杂螺[4.5]癸烷-2-甲酸基酯的制备方法
CN111763228A (zh) * 2020-08-03 2020-10-13 连云港宏业化工有限公司 （3s）-4-氯-3-[（三甲基甲硅烷基）氧基]丁腈合成方法
WO2025087822A1 (fr) 2023-10-23 2025-05-01 F. Hoffmann-La Roche Ag Nouveau procédé de préparation de chlorhydrate de (3r)-fluoropyrrolidine

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