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WO2009011551A2 - Procédé efficace pour la préparation de 3-hydroxy-pyrrolidine et de ses dérivés - Google Patents

Procédé efficace pour la préparation de 3-hydroxy-pyrrolidine et de ses dérivés Download PDF

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Publication number
WO2009011551A2
WO2009011551A2 PCT/KR2008/004193 KR2008004193W WO2009011551A2 WO 2009011551 A2 WO2009011551 A2 WO 2009011551A2 KR 2008004193 W KR2008004193 W KR 2008004193W WO 2009011551 A2 WO2009011551 A2 WO 2009011551A2
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
added
hydroxypyrrolidine
Prior art date
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Ceased
Application number
PCT/KR2008/004193
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English (en)
Other versions
WO2009011551A3 (fr
Inventor
Long Guo Quan
Jae Kwan Lee
Mei Hua Hong
Kwang Sub Kim
Kwang Sik Park
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RSTECH Corp
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RSTECH Corp
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Filing date
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Publication of WO2009011551A2 publication Critical patent/WO2009011551A2/fr
Publication of WO2009011551A3 publication Critical patent/WO2009011551A3/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 3-hydroxypyrrolidine and derivatives thereof having high chemical and optical purity. More particularly, the present invention relates to an efficient process for the preparation of optically pure 3-hydroxypyrrolidine and derivatives thereof in an industrial mass production manner and without reduction of optical purity.
  • 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.
  • Optically active chiral JV-benzyl- 3-hydroxypyrrolidine was prepared from racemic N - benzyl-3-hydroxypyrrolidine by stereoselectively esterifying one isomer of the racemate using enzymes or microorganisms [Japanese Patent No. Hei 6-211782; Japanese Patent No. Hei 6-141876; Japanese Patent No. Hei 4-131093].
  • the chiral N - substituted-3-hydroxypyrrolidine was also prepared through stereoselective hydrolysis of any one isomer of racemic ./V-substituted-3-acyloxypyrrolidine using enzymes or microorganisms [WO 95/03421; Japanese Patent No. Hei 7-116138; Japanese Patent No.
  • an object of the present invention is to provide a novel and effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof.
  • Another object of the present invention is to provide an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof having optical purity of 99.0%ee or more without substantive deterioration of the optical purity of the starting material.
  • Another object of the present invention is to provide an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof that is adequate for industrial mass production and provides safe working condition and high optical purity.
  • a method for preparing 3-hydroxypyrrolidine and derivatives thereof comprising (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid ester, (b) reducing an ester group of the compound obtained from the step (a), (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3 -hyrdroxy -protected pyrrolidine, and (e) deprotecting the compound obtained from the step (d) to produce a targeted compound.
  • the method for preparing 3-hydroxypyrrolidine and derivatives thereof of the present invention provides 3-hydroxypyrrolidine and derivatives with high optical purity without substantive deterioration of the optical purity of the starting material.
  • the chiral compound of formula 2, which is the starting material gave 3-hydroxypyrrolidine and derivatives with high optical purity having 99%ee or more, without substantive reduction of the optical purity.
  • 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. This simplifies the reaction process and improves the production yield. Further, the overall processes of the present invention are carried out in a simple and mild condition. This means that the method of the present invention is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.
  • the present invention relates to an effective process for the preparation of
  • 3-hydroxypyrrolidine and derivatives thereof comprising the steps of (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by formula 2, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hyrdroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine and derivatives thereof having formula 1:
  • R represents an ester formation group, preferably C ⁇ C alkyl group, more preferably ethyl group or methyl group.
  • R represents hydrogen, C -C alkyl, C -C cycloalkyl, C -C alkoxy, C -C aryl, C -C heteroaryl, C -C aralkyl, C -
  • the hydroxyl protecting group methoxymethyl, benzy- loxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t- butylcarbonyl, and benzoyl can be mentioned.
  • the hydroxyl protecting group is t-butyl. Hydroxy-protection using the t-butyl group can be performed by reacting the 4-halo-3-hydroxybutyric acid ester with isobutylene in a presence of acid as a catalyst.
  • hydroxy- protection of the 4-halo-3-hydroxybutyric acid ester using the t-butyl group gave various advantages such as high reaction yield and convenience of deprotection.
  • the acid catalyst inorganic acid, organic acid and acidic ion exchange resin can be used. But it is not particularly limited thereto.
  • the acid catalyst can be used in a single or combined mode.
  • the amount of the acid catalyst to be used is in a range of 0.01-0.5 equivalents, preferably 0.01-2 equivalents, most preferably 0.05-0.015 equivalents, based on 4-halo-3-hydroxybutyric acid ester.
  • An organic solvent that can be used in the protection reaction is not particularly limited, and any one that is common in the art can be used.
  • organic solvent examples include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, esters and ethers.
  • aromatic organic solvents such as toluene and benzene, halogenated alkane such as dichloromethane, dichloroethane and chloroform, ethers such as ethyl acetate and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used.
  • Reaction temperature is preferably in the range of 0 to 5O 0 C. More preferable is 10 to 4O 0 C.
  • the compound of formula 3 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification (e.g., fractional distillation or re- crystallization). This provides the simplification of the processes and the improvement of the production yield.
  • 4-halo- 3 -hydroxy -protected butyric acid ester having formula 3 is obtained.
  • X and R is the same as defined in formula 2, and P means a hydroxyl protecting group such as methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t- butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t-butylcarbonyl, and benzoyl, preferably t-butyl.
  • P means a hydroxyl protecting group such as methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t- butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t-butylcarbonyl,
  • [37] 4-halo-3-hydroxy-protected butyric acid ester represented by formula 3 is converted to the corresponding primary alcohol compound.
  • the reducing agent to be used in the reduction reaction borane-methylsulfide complex, borane- tetrahydrofuran complex, diborane, lithium aluminum hydride or borohydride metal salt can be mentioned.
  • an activating agent which is well known in the art can be also used.
  • boron trifluoride diethyl etherate, calcium chloride, lithium chloride, iodide (I ) and methyl alcohol can be mentioned.
  • Preferable is the mixture of borohydride metal salt and boron trifluoride diethyl etherate.
  • the borohydride metal salt is used in an amount of 0.5-2.0 equivalents, preferably 0.8-1.5 equivalents, based on the compound of formula 3.
  • the activating agent is used in an amount of 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents, based on the borohydride metal salt.
  • a solvent that can be used in the reduction reaction is not particularly limited, and any one that is common in the art can be used. Specifically, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers and alcohols can be used. Among them, non-toxic and cost effective organic solvent is preferable. For example, toluene, isopropanol, tetrahydrofuran and dioxane may be used.
  • the amount of the solvent to be used is 1-10 times based on the weight of the compound of formula 3. Preferable is 2-5 times.
  • Reaction temperature is preferably in the range of 0 to 100 0 C. More preferable is 20 to 5O 0 C.
  • a primary alcohol having formula 4 is obtained.
  • the compound of formula 4 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification.
  • the compound of formula 4 is converted to the corresponding sulfonate compound by the reaction with the sulfonyl halide.
  • the sulfonyl halide is represented by R SO X (wherein, R is C -C alkyl; C -C aryl; C -C alkyl substituted with nitro, methyl, ethyl, cyano, fluoro or chloro group; or C -C aryl substituted with nitro, methyl, ethyl, cyano, fluoro or chloro group, and X is F, Cl, Br or I).
  • methanesulfonyl chloride MsCl
  • p-toluenesulfonyl chloride TsCl
  • benzenesulfonyl chloride trifluoromethanesulfonyl chloride or nitrobenzenesulfonyl chloride
  • the above reaction is typically performed in a presence of a base.
  • a base imidazole, 2,6-lutidine, JV,./V-dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof can be mentioned.
  • 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 compound of formula 4.
  • An organic solvent that can be used in the reaction is not particularly limited, and any one that is common in the art can be used.
  • the organic solvent include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and ethers. Specifically, aromatic organic solvents such as toluene and benzene, halogenated alkanes 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 -20 to 4O 0 C, more preferably of 0 to 4O 0 C.
  • the compound of formula 5 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without
  • the above reaction is preferably carried out in a presence of a base.
  • Inorganic base or organic base may be used.
  • the inorganic base to be used includes carbonate salts, bi- carbonate salts or hydroxides of an alkali metal salt or an alkali earth metal.
  • lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide or calcium hydroxide can be used.
  • As an organic base trialkylamine above mentioned can be used.
  • the base is added in an amount of 1 - 10 equivalents, preferably in an amount of 1-5 equivalents, most preferably 1.1-2 equivalents based on the compound of formula 5.
  • the solvent to be include alcohols, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and ethers. Specifically, alcohols such as methyl alcohol, ethyl alcohol and isopropanol, aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used. Preferable are alcohols. Reaction temperature is preferably in the range of 0 to 100 0 C. More preferable is room temperature to 8O 0 C. The compound of formula 6 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification.
  • the targeted 3-hydroxypyrrolidine or derivative thereof is obtained.
  • the reaction conditions of the deprotection reaction are well known in the art.
  • the acid to be used is not particularly limited. In terms of practical points, inorganic acid is preferable. Among them, HCl and H SO are more preferable.
  • the acid can be used in a single or combined manner.
  • the acid is used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, most preferably 1 to 1.3 equivalents, based on the compound of formula 6.
  • Reaction temperature is preferably in the range of 0 to 100 0 C. More preferable is room temperature to 8O 0 C.
  • the reaction is typically carried out in water, but organic solvent or mixture of the organic solvent and water can be also used.
  • organic side products are removed by extraction using organic solvent.
  • the solvent to be used for the extraction is an aromatic organic solvent such as toluene or benzene, a halogenated alkane such as dichloromethane, dichloroethane or chloroform, and an ether such as ethyl ether, and an ester such as ethyl acetate.
  • Free base of the targeted compound is obtainable by treating the obtained crude products with inorganic base in an amount of 0.8 to 5 equivalents, followed by filtration of inorganic salt or extraction by organic solvent.
  • the organic base to be used is carbonate salt or hydroxide of an alkali metal salt or an alkali earth metal. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide or calcium hydroxide can be used.
  • an organic base trialkylamine above mentioned can be used.
  • Example 1 [70] To a high pressure reactor, toluene 581 mL, ethyl S-4-chloro-3-hydroxybutyric acid ester 250.1 g (1.501 mol, optical purity 99.3%ee) and H SO 14.7 g (0.15 mol) were added, and then isobutylene 191.2 g (3.407 mol) was slowly added thereto at O 0 C. Thereafter, the reactor was closed and reaction was performed at 24 0 C for 24 hours. The reaction pressure was 2 bars. Reaction mixture was cooled to 1O 0 C and high pressure was released. Aqueous solution 461 g of NaHCO 37.8 g (0.45 mol) was added to the reaction mixture and stirred for additional 30 minutes.

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

Abstract

La présente invention concerne un procédé efficace pour la préparation de 3-hydroxy-pyrrolidine ou de ses dérivés. Ce procédé comporte plusieurs opérations: (a) protection d'un groupe hydroxyle d'un acide 4-halo-3-hydroxy-butyrique; (b) réduction d'un groupe ester du composé issu de (a) donnant un composé alcool correspondant; (c) réaction du composé issu de (b) avec un halogénure sulfonyle donnant un composé sulfonate correspondant; (d) réaction du composé issu de (c) avec une amine donnant un composé pyrrolidine 3-hydroxy-protégé; et (e), déprotection du composé issu de (d) produisant la 3-hydroxy-pyrrolidine ciblée ou des dérivés de celle-ci. Le procédé donne une 3-hydroxy-pyrrolidine, ou des dérivés de celle-ci, d'une grande pureté optique étant donné que la pureté optique du matériau de départ est sensiblement conservée. Dans ce procédé, chacune des opérations s'exécute dans des conditions moyennes, sans qu'il y ait besoin d'une quelconque purification spéciale. Cela signifie que le procédé convient et est approprié pour une production industrielle de masse de 3-hydroxy-pyrrolidine et de dérivés de celle-ci d'une grande pureté optique.
PCT/KR2008/004193 2007-07-18 2008-07-17 Procédé efficace pour la préparation de 3-hydroxy-pyrrolidine et de ses dérivés Ceased WO2009011551A2 (fr)

Applications Claiming Priority (2)

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KR1020070071902A KR100915551B1 (ko) 2007-07-18 2007-07-18 3-히드록시 피롤리딘 및 이의 유도체의 효율적 제조방법
KR10-2007-0071902 2007-07-18

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WO2009011551A2 true WO2009011551A2 (fr) 2009-01-22
WO2009011551A3 WO2009011551A3 (fr) 2009-03-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015099126A1 (fr) * 2013-12-27 2015-07-02 株式会社エーピーアイ コーポレーション Procédé de production d'acide 5-hydroxypipéridine-2-carboxylique

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101858615B1 (ko) 2017-09-28 2018-06-28 정영걸 구강 세정기에 부착되는 세정 브러쉬
KR102120153B1 (ko) 2018-05-18 2020-06-08 정영걸 세정액 공급부재에 연결되는 수동식 세정 브러쉬

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60104061A (ja) 1983-11-08 1985-06-08 Sankyo Co Ltd ピロリジン誘導体の製法
JPH0776209B2 (ja) * 1990-04-11 1995-08-16 高砂香料工業株式会社 光学活性３―ヒドロキシピロリジン誘導体の製造方法
JP2005281168A (ja) * 2004-03-29 2005-10-13 Daiso Co Ltd ３−ピロリジノールの製造法

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015099126A1 (fr) * 2013-12-27 2015-07-02 株式会社エーピーアイ コーポレーション Procédé de production d'acide 5-hydroxypipéridine-2-carboxylique
CN105899487A (zh) * 2013-12-27 2016-08-24 株式会社Api 5-羟基哌啶-2-甲酸的制造方法
JPWO2015099126A1 (ja) * 2013-12-27 2017-03-23 株式会社エーピーアイ コーポレーション ５−ヒドロキシピペリジン−２−カルボン酸の製造方法
US9790181B2 (en) 2013-12-27 2017-10-17 Api Corporation Method for producing 5-hydroxypiperidine-2-carboxylic acid
CN107573277A (zh) * 2013-12-27 2018-01-12 株式会社Api 5‑羟基哌啶‑2‑甲酸的制造方法
US9988351B2 (en) 2013-12-27 2018-06-05 Api Corporation Method for producing 5-hydroxypiperidine-2-carboxylic acid
CN105899487B (zh) * 2013-12-27 2018-10-19 株式会社Api 5-羟基哌啶-2-甲酸的制造方法
US10370330B2 (en) 2013-12-27 2019-08-06 Api Corporation Method for producing 5-hydroxypiperidine-2-carboxylic acid
US10703719B2 (en) 2013-12-27 2020-07-07 Api Corporation Method for producing 5-hydroxypiperidine-2-carboxylic acid
CN111499562A (zh) * 2013-12-27 2020-08-07 株式会社Api 5-羟基哌啶-2-甲酸的制造方法
CN107573277B (zh) * 2013-12-27 2020-10-16 株式会社Api 5-羟基哌啶-2-甲酸的制造方法
CN111499562B (zh) * 2013-12-27 2023-12-26 株式会社Api 5-羟基哌啶-2-甲酸的制造方法

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KR100915551B1 (ko) 2009-09-10
KR20090008725A (ko) 2009-01-22

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