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WO2014035107A1 - Procédé de purification de base libre de fluvoxamine et procédé de préparation de maléate de fluvoxamine de haute pureté l'utilisant - Google Patents

Procédé de purification de base libre de fluvoxamine et procédé de préparation de maléate de fluvoxamine de haute pureté l'utilisant Download PDF

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Publication number
WO2014035107A1
WO2014035107A1 PCT/KR2013/007647 KR2013007647W WO2014035107A1 WO 2014035107 A1 WO2014035107 A1 WO 2014035107A1 KR 2013007647 W KR2013007647 W KR 2013007647W WO 2014035107 A1 WO2014035107 A1 WO 2014035107A1
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WO
WIPO (PCT)
Prior art keywords
fluvoxamine
free base
water
reaction mixture
organic solvent
Prior art date
Application number
PCT/KR2013/007647
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English (en)
Korean (ko)
Inventor
전성현
유혜심
성진의
서경재
Original Assignee
주식회사 에스텍파마
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 주식회사 에스텍파마 filed Critical 주식회사 에스텍파마
Priority to JP2015529666A priority Critical patent/JP6228210B2/ja
Priority to CN201380045113.7A priority patent/CN104703967B/zh
Publication of WO2014035107A1 publication Critical patent/WO2014035107A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/58—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/14—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the present invention relates to a method for purifying fluvoxamine free base comprising converting fluvoxamine free base to fluvoxamine tartrate and a method for producing high purity fluvoxamine maleate using the same.
  • Fluvoxamine maleate is a compound having the structure of Formula 1, which is useful for the treatment of depression and major depressive disorders by regulating serotonin concentration through 5HT4-receptor antagonism and selective serotonin reuptake inhibition. do.
  • U.S. Patent No. 4,085,225 discloses fluvoxamine maleate and its preparation.
  • U.S. Patent No. 4,085,225 discloses a preparation method comprising reacting 5-methoxy-4'-trifluoromethylvalerophenone oxime with 2-chloroethylamine hydrochloride, the final product being obtained, namely flu radiation.
  • Minalate is purified by recrystallization from acetonitrile.
  • an organic solvent such as acetonitrile
  • the purity of fluvoxamine maleate is relatively low (HPLC purity: about 97.3%).
  • U. S. Patent No. 6,433, 225 discloses an improved method for producing fluvoxamine.
  • U. S. Patent No. 6,433, 225 includes reacting 5-methoxy-4'-trifluoromethylvalerophenone oxime with 2-chloroethylamine hydrochloride in the presence of a base in a water-immiscible organic solvent.
  • Fluvoxamine maleate obtained in the final step is subjected to a purification step through many unit operations such as filtration, toluene washing, drying, recrystallization with water, filtration, washing with cold water, and drying.
  • the present inventors have conducted various studies to develop a method for producing fluvoxamine maleate having high purity, that is, 99% or more HPLC purity, in which organic softeners and residual solvents are essentially removed.
  • the inventors have found that the purity of fluvoxamine maleate has a decisive effect on the purity of the fluvoxamine free base used to form the maleate salt.
  • the inventors have found that the purity of fluvoxamine free base when converting crude fluvoxamine free base to fluvoxamine tartrate (fluvoxamine tartrate) and then back to fluvoxamine free base was found to increase significantly, and when converted to the maleate salt form it was found that fluvoxamine maleate with an HPLC purity of at least 99% could be prepared.
  • an object of the present invention is to provide a method for purifying fluvoxamine free base, which comprises converting fluvoxamine to tartarate.
  • step (b) (i) filtering the reaction mixture of step (a) and then drying the obtained solid to obtain tartarate of fluvoxamine, or (ii) filtering the reaction mixture of step (a), and then Slurrying in the water-miscible organic solvent used in step (a), filtering the obtained slurry, and then drying the obtained solid to obtain tartarate of fluvoxamine;
  • step (c) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent;
  • step (d) separating the organic layer from the reaction mixture obtained in step (c), and then concentrating the separated organic layer to obtain fluvoxamine free base.
  • the tartaric acid may be preferably L-(+)-tartaric acid
  • the water-miscible organic solvent used in step (a) may be preferably acetone.
  • Step (a) is followed by stirring the reaction mixture obtained by reacting the crude fluvoxamine free base in an aqueous solution of tartaric acid with a water-miscible organic solvent for 30 minutes to 2 hours at 40 to 45 ° C., followed by 30 minutes to 1 hour at room temperature. It may further comprise a step of stirring.
  • the water-immiscible organic solvent used in step (c) may preferably be ethyl acetate.
  • a method for obtaining fluvoxamine free base according to the above purification method; (q) reacting the fluvoxamine free base obtained in step (p) with maleic acid in water; And (r) filtering the reaction mixture obtained in step (q), and then drying the obtained solid to obtain fluvoxamine maleate.
  • the step (r) may be preferably carried out by filtering the reaction mixture obtained in step (q), then washing the obtained solid with water of 5 to 10 ° C. and then drying.
  • the purity of the fluvoxamine free base when the crude fluvoxamine free base is converted to fluvoxamine tartrate (fluvoxamine tartrate) and then back to the fluvoxamine free base has been found to increase significantly.
  • fluvoxamine free base obtained by the above purification method is converted into the maleate salt form, fluvoxamine maleate having an HPLC purity of 99% or more can be prepared.
  • the method for producing fluvoxamine maleate according to the present invention is simply cold water (for example, water of 5 to 10 °C), without performing a recrystallization process using an organic solvent (for example, acetonitrile) or water.
  • High purity fluvoxamine maleate can be prepared by washing with.
  • the present invention provides a method for purifying fluvoxamine free base comprising the following steps:
  • step (b) (i) filtering the reaction mixture of step (a) and then drying the obtained solid to obtain tartarate of fluvoxamine, or (ii) filtering the reaction mixture of step (a), and then Slurrying in the water-miscible organic solvent used in step (a), filtering the obtained slurry, and then drying the obtained solid to obtain tartarate of fluvoxamine;
  • step (c) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent;
  • step (d) separating the organic layer from the reaction mixture obtained in step (c), and then concentrating the separated organic layer to obtain fluvoxamine free base.
  • Purification methods of the present invention include the conversion of crude fluvoxamine free base to tartrate of fluvoxamine.
  • Fluvoxamine tartrate (fluvoxamine tartrate) has low solubility in organic solvents such as acetone, ethyl acetate, ether, methanol, ethanol, isopropyl alcohol, and can be easily obtained in high yield and high purity through recrystallization. have.
  • the fluvoxamine free base in oil form has no method of purification other than column chromatography, but since the tartarate of fluvoxamine is in a solid form rather than an oil form, it is inefficient for column production. You can easily get it without the use of.
  • the purification method of the present invention comprises the step of reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent (ie, step (a)).
  • the crude fluvoxamine free base can be prepared according to the method disclosed in prior art, for example US Pat. No. 4,085,225, and is usually obtained in an oil phase having an HPLC purity of about 80-95%.
  • the tartaric acid aqueous solution may be obtained by dissolving tartaric acid in water, wherein the amount of tartaric acid may be used in an amount of 0.9 to 1.2 moles, preferably 0.98 to 1.2 moles with respect to 1 mole of crude fluvoxamine free base.
  • the amount of water used in the preparation of the aqueous tartaric acid solution is not particularly limited, for example, it can be used in the range of 1 to 4 parts by weight based on 1 part by weight of tartaric acid.
  • the tartaric acid may use all of L-(+)-tartaric acid, D-(-)-tartaric acid, DL-tartaric acid, and L-(+)-tartaric acid may be particularly preferably used in terms of yield and purity.
  • the water-miscible organic solvent used in step (a) may be acetone, acetonitrile, tetrahydrofuran, etc., preferably acetone.
  • the reaction mixture obtained in step (a) can be used directly in the process of step (b).
  • the precipitate present in the reaction mixture of step (a) is produced in the form of fine particles, and the subsequent filtration in step (b) may take a long time.
  • step (a) is agitated the reaction mixture obtained by reacting the crude fluvoxamine free base in an aqueous tartaric acid solution with a water-miscible organic solvent at 40-45 ° C. for 30 minutes to 2 hours. Then, the method may further include stirring at room temperature for 30 minutes to 1 hour.
  • the purification method of the present invention comprises the step of obtaining tartarate of fluvoxamine, that is, step (b).
  • Step (b) can isolate the tartarate of fluvoxamine by filtering the reaction mixture of step (a) and then drying the obtained solid; Also optionally filtering the reaction mixture of step (a), and then the solid obtained is slurried in the water-miscible organic solvent used in step (a) (ie dispersed in an organic solvent) and the slurry obtained is filtered Next, the tartarate of fluvoxamine can be isolated by drying the obtained solid.
  • step (b) can isolate the tartarate of fluvoxamine by filtering the reaction mixture of step (a) and then drying the obtained solid; Also optionally filtering the reaction mixture of step (a), and then the solid obtained is slurried in the water-miscible organic solvent used in step (a) (ie dispersed in an organic solvent) and the slurry obtained is filtered Next, the tartarate of fluvoxamine can be isolated
  • the purification method of the present invention comprises the step of converting the tartarate of fluvoxamine to fluvoxamine free base, ie step (c).
  • Step (c) can be carried out by reacting the tartarate of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent.
  • the water-immiscible organic solvent may be ethyl acetate, dichloromethane, diethyl ether, and the like, preferably ethyl acetate.
  • the purification method of the present invention also includes a process for isolating the obtained fluvoxamine free base, that is, step (d).
  • Step (d) may be carried out by separating the organic layer from the reaction mixture obtained in step (c), and then concentrating the separated organic layer.
  • the product obtained by this concentration ie, purified fluvoxamine free base
  • the product obtained can be used directly, ie in situ, for the production of high purity fluvoxamine maleate.
  • the present invention includes a method for producing fluvoxamine maleate including the purification step.
  • the fluvoxamine free base obtained from the purification process can be carried out according to known methods, for example, the maleate salt conversion method disclosed in US Pat. No. 4,085,225, US Pat. No. 6,433,225, and the like.
  • the fluvoxamine free base obtained by carrying out the purification process according to the present invention does not require a recrystallization step using an organic solvent, and furthermore does not perform a recrystallization step in water, and can simply carry out high purity fluvoxamine maleate. It can manufacture.
  • step (p) obtaining a fluvoxamine free base according to the purification method; (q) reacting the fluvoxamine free base obtained in step (p) with maleic acid in water; And (r) filtering the reaction mixture obtained in step (q), and then drying the obtained solid to obtain fluvoxamine maleate.
  • Step (r) may be preferably carried out by filtering the reaction mixture obtained in step (q), then washing the obtained solid with water of 5 to 10 ° C. and then drying.
  • the crude fluvoxamine free base used as starting material in the following examples was prepared according to the method disclosed in US Pat. No. 4,085,225 (Example 6).
  • Dimethylformamide (12.5 L) in 5-methoxy-4'-trifluoromethylvalerophenone oxime (5.0 mol, 1.3 kg), 2-chloroethylamine hydrochloride (5.2 mol, 0.6 kg), and hydroxide Potassium (0.7 kg) was added with stirring at 10 ° C in turn.
  • the reaction mixture was stirred for 2 days at room temperature and then concentrated in vacuo to remove dimethylformamide.
  • the obtained residue was poured into water, and 2N hydrochloric acid was added until pH 3.
  • Fluvoxamine D-tartrate was carried out in the same manner as in Step 1 of Example 1, except that D-(-)-tartaric acid (57.7 g, 0.385 mol) was used instead of L-(+)-tartaric acid. 144.3 g were obtained (yield: 80%, HPLC purity: 98.1%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de purification de base libre de fluvoxamine, comprenant la conversion de base libre de fluvoxamine brute en tartrate de fluvoxamine. De plus, la présente invention concerne un procédé de préparation de maléate de fluvoxamine à l'aide du procédé de purification.
PCT/KR2013/007647 2012-08-29 2013-08-27 Procédé de purification de base libre de fluvoxamine et procédé de préparation de maléate de fluvoxamine de haute pureté l'utilisant WO2014035107A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2015529666A JP6228210B2 (ja) 2012-08-29 2013-08-27 フルボキサミン遊離塩基の精製方法およびそれを用いた高純度フルボキサミンマレイン酸塩の製造方法
CN201380045113.7A CN104703967B (zh) 2012-08-29 2013-08-27 氟伏沙明游离碱的精制方法及利用其的高纯度马来酸氟伏沙明的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0094690 2012-08-29
KR1020120094690A KR101427221B1 (ko) 2012-08-29 2012-08-29 플루복사민 자유 염기의 정제방법 및 이를 이용한 고순도 플루복사민 말레이트의 제조방법

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JP (1) JP6228210B2 (fr)
KR (1) KR101427221B1 (fr)
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Cited By (1)

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CN116023296A (zh) * 2022-12-29 2023-04-28 上海国创医药股份有限公司 一种马来酸氟伏沙明的制备方法

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CN112494445A (zh) * 2020-12-11 2021-03-16 丽珠集团丽珠制药厂 一种马来酸氟伏沙明组合物及其制备方法
CN116947691B (zh) * 2023-08-09 2024-04-02 山东锐顺药业有限公司 一种马来酸氟伏沙明的制备方法

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KR900001420B1 (ko) * 1983-11-22 1990-03-09 루드빅 허이만 운트 콤파니 게엠베하 4-아미노-6,7-디메톡시2-[4-(푸로-2-일)-피페라진-1-일]-퀴나졸린 및 생리적으로 적합한 그염의 제조방법
KR950000778B1 (ko) * 1989-09-28 1995-02-02 호꾸리꾸 세이야꾸 가부시끼가이샤 광학적 활성 벤질 알코올 화합물 및 그의 이용
US6433225B1 (en) * 1999-11-12 2002-08-13 Sun Pharamaceutical Industries, Ltd. Process for the preparation of fluvoxazmine maleate
KR20050043776A (ko) * 2001-11-08 2005-05-11 세프라코 아이엔시. 거울상 이성질체로 농축된, 시탈로프람의 데스메틸 및디데스메틸 대사물을 이용한 우울증 및 다른 중추신경계질환 치료방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116023296A (zh) * 2022-12-29 2023-04-28 上海国创医药股份有限公司 一种马来酸氟伏沙明的制备方法
CN116023296B (zh) * 2022-12-29 2023-07-07 上海国创医药股份有限公司 一种马来酸氟伏沙明的制备方法

Also Published As

Publication number Publication date
KR20140028433A (ko) 2014-03-10
CN104703967A (zh) 2015-06-10
JP6228210B2 (ja) 2017-11-08
KR101427221B1 (ko) 2014-08-13
CN104703967B (zh) 2017-03-15
JP2015526507A (ja) 2015-09-10

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