WO2014035107A1 - Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same - Google Patents
Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same Download PDFInfo
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- 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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- 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
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- 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
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- 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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Abstract
The present invention provides a method for purifying fluvoxamine free base, comprising the conversion of crude fluvoxamine free base into fluvoxamine tartrate. In addition, the present invention provides a method for preparing fluvoxamine maleate using the purification method.
Description
본 발명은 플루복사민 자유 염기를 플루복사민 타르트레이트로 전환하는 것을 포함하는 플루복사민 자유 염기의 정제방법 및 이를 이용한 고순도 플루복사민 말레이트의 제조방법에 관한 것이다.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.
플루복사민 말레이트(fluvoxamine maleate)는 하기 화학식 1의 구조를 갖는 화합물로서, 5HT4-수용체 길항 작용 및 선택적 세로토닌 재흡수 억제 작용을 통하여 세로토닌 농도를 조절함으로써 우울증 및 주요 우울증 장애의 치료에 유용하게 사용된다. 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.
<화학식 1><Formula 1>
미국특허 제4,085,225호는 플루복사민 말레이트 및 이의 제조방법을 개시하고 있다. 미국특허 제4,085,225호는 5-메톡시-4'-트리플루오로메틸발레로페논 옥심과 2-클로로에틸아민 염산염을 반응시키는 것을 포함하는 제조방법을 개시하고 있으며, 최종적으로 얻어지는 생성물 즉, 플루복사민 말레이트는 아세토니트릴로부터 재결정하여 정제된다. 그러나, 최종 단계에서 아세토니트릴과 같은 유기용매를 사용함으로써 잔류용매의 문제점이 있으며, 특히 플루복사민 말레이트의 순도가 상대적으로 낮다(HPLC 순도: 약 97.3%)는 문제가 있다. 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. However, there is a problem of residual solvent by using an organic solvent such as acetonitrile in the final step, in particular, the purity of fluvoxamine maleate is relatively low (HPLC purity: about 97.3%).
미국특허 제6,433,225호는 개선된 플루복사민의 제조방법을 개시하고 있다. 상기 미국특허 제6,433,225호는 5-메톡시-4'-트리플루오로메틸발레로페논 옥심과 2-클로로에틸아민 염산염을 염기 존재하에서 수-비혼화성 유기용매 중에서 반응시키는 것을 포함한다. 최종 단계에서 얻어진 플루복사민 말레이트는 여과, 톨루엔 세척, 건조, 물을 사용한 재결정, 여과, 차가운 물로 세척, 및 건조 등의 많은 단위 조작을 통하여 정제 단계를 수행한다. 그러나, 반응 중간 단계에서 정제과정이 없고 최종 화합물을 물에서의 재결정을 통하여 정제함으로써, 반응중 생성되는 많은 유기 유연물질의 정제가 어려워 고순도의 플루복사민 말레이트를 얻기에는 한계가 있다. 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. However, since there is no purification step in the middle of the reaction and the final compound is purified through recrystallization in water, it is difficult to purify many organic flexible substances generated during the reaction, and thus there is a limit in obtaining high purity fluvoxamine maleate.
본 발명자들은 유기 유연물질 및 잔류 용매가 근본적으로 제거된 고순도 즉, 99% 이상의 HPLC 순도를 갖는 플루복사민 말레이트의 제조방법을 개발하고자 다양한 연구를 수행하였다. 본 발명자들은 플루복사민 말레이트의 순도가 말레이트염 형성에 사용되는 플루복사민 자유 염기의 순도에 결정적인 영향을 미친다는 것을 발견하였다. 특히, 본 발명자들은 조(crude) 플루복사민 자유 염기를 플루복사민의 타르타르산염(플루복사민 타르트레이트)으로 전환한 후, 다시 플루복사민 자유 염기로 전환할 경우, 플루복사민 자유 염기의 순도가 현저하게 증가한다는 것을 발견하였으며, 이를 말레이트염 형태로 전환할 경우 99% 이상의 HPLC 순도를 갖는 플루복사민 말레이트를 제조할 수 있다는 것을 발견하였다.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. In particular, 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.
따라서, 본 발명은 플루복사민의 타르타르산염으로의 전환을 포함하는 플루복사민 자유 염기의 정제방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a method for purifying fluvoxamine free base, which comprises converting fluvoxamine to tartarate.
또한, 본 발명은 상기 정제방법으로부터 얻어진 플루복사민 자유 염기로부터 고순도의 플루복사민 말레이트를 제조하는 방법을 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide a method for producing high purity fluvoxamine maleate from fluvoxamine free base obtained from the above purification method.
본 발명의 일 태양에 따라, 하기 단계를 포함하는 플루복사민 유리 염기의 정제방법이 제공된다:According to one aspect of the invention, there is provided a process for purifying fluvoxamine free base, comprising the following steps:
(a) 조(crude) 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시키는 단계;(a) reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent;
(b) (i) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻거나, 혹은 (ii) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 단계(a)에서 사용된 수-혼화성 유기용매 중에서 슬러리화하고, 얻어진 슬러리를 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻는 단계;(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;
(c) 단계(b)에서 얻어진 플루복사민의 타르타르산염을 수산화나트륨 수용액과 수-비혼화성 유기용매 중에서 반응시키는 단계; 및(c) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent; And
(d) 단계(c)에서 얻어진 반응 혼합물로부터 유기층을 분리한 후, 분리된 유기층을 농축하여 플루복사민 유리염기를 얻는 단계.(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.
본 발명의 제조방법에 있어서, 상기 타르타르산은 바람직하게는 L-(+)-타르타르산일 수 있으며, 단계(a)에서 사용되는 상기 수-혼화성 유기용매는 바람직하게는 아세톤일 수 있다. 단계(a)는 조 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시켜 얻어진 반응 혼합물을 40∼45 ℃에서 30분 내지 2 시간 동안 교반한 다음, 실온에서 30분 내지 1 시간 동안 교반하는 공정을 추가로 포함할 수 있다. 또한, 단계(c)에서 사용되는 상기 수-비혼화성 유기용매는 바람직하게는 에틸 아세테이트일 수 있다.In the preparation method of the present invention, the tartaric acid may be preferably L-(+)-tartaric acid, and 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. In addition, the water-immiscible organic solvent used in step (c) may preferably be ethyl acetate.
본 발명의 다른 태양에 따라, 상기 정제방법에 따라 플루복사민 유리 염기를 얻는 단계; (q) 단계(p)에서 얻어진 플루복사민 유리 염기를 말레인산과 물 중에서 반응시키는 단계; 및 (r) 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민 말레이트를 얻는 단계를 포함하는, 플루복사민 말레이트의 제조방법이 제공된다.According to another aspect of the present invention, there is provided 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.
상기 단계(r)은 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 5∼10 ℃의 물로 세척한 후, 건조함으로써 바람직하게 수행될 수 있다.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.
본 발명에 의해, 조(crude) 플루복사민 자유 염기를 플루복사민의 타르타르산염(플루복사민 타르트레이트)으로 전환한 후, 다시 플루복사민 자유 염기로 전환할 경우, 플루복사민 자유 염기의 순도가 현저하게 증가한다는 것이 밝혀졌다. 또한, 상기 정제방법에 의해 얻어진 플루복사민 자유 염기를 말레이트염 형태로 전환할 경우 99% 이상의 HPLC 순도를 갖는 플루복사민 말레이트를 제조할 수 있다는 것이 밝혀졌다. 또한, 본 발명에 따른 플루복사민 말레이트의 제조방법은 유기용매(예를 들어, 아세토니트릴) 또는 물을 사용한 재결정 공정을 수행하지 않고도, 간단히 차가운 물(예를 들어 5∼10 ℃의 물)로 세척함으로써 높은 순도의 플루복사민 말레이트를 제조할 수 있다.According to the present invention, 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. In addition, it has been found that when the 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. In addition, the method for producing fluvoxamine maleate according to the present invention is simply cold water (for example, water of 5 to 10 ℃), without performing a recrystallization process using an organic solvent (for example, acetonitrile) or water. High purity fluvoxamine maleate can be prepared by washing with.
본 발명은 하기 단계를 포함하는 플루복사민 유리 염기의 정제방법이 제공한다:The present invention provides a method for purifying fluvoxamine free base comprising the following steps:
(a) 조(crude) 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시키는 단계;(a) reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent;
(b) (i) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻거나, 혹은 (ii) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 단계(a)에서 사용된 수-혼화성 유기용매 중에서 슬러리화하고, 얻어진 슬러리를 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻는 단계;(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;
(c) 단계(b)에서 얻어진 플루복사민의 타르타르산염을 수산화나트륨 수용액과 수-비혼화성 유기용매 중에서 반응시키는 단계; 및(c) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent; And
(d) 단계(c)에서 얻어진 반응 혼합물로부터 유기층을 분리한 후, 분리된 유기층을 농축하여 플루복사민 유리염기를 얻는 단계.(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.
본 발명의 정제방법은 조 플루복사민 유리 염기를 플루복사민의 타르타르산염으로 전환하는 것을 포함한다. 플루복사민의 타르타르산염(플루복사민 타르트레이트)은 아세톤, 에틸 아세테이트, 에테르, 메탄올, 에탄올, 이소프로필알콜 등의 유기용매에 대한 용해도가 매우 낮기 때문에 재결정 방법을 통하여 손쉽게 고수율 및 고순도로 얻을 수 있다. 특히, 오일 형태인 플루복사민 유리 염기는 컬럼 크로마토그래피법(column chromatography) 외에는 달리 정제할 방법이 없으나, 플루복사민의 타르타르산염은 오일 형태가 아닌 고체 형태이므로, 대상생산에 비효율적인 컬럼 크로마토그래피법의 사용 없이도 쉽게 얻을 수 있다.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. In particular, 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.
본 발명의 정제방법은 조(crude) 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시키는 단계[즉, 단계(a)]를 포함한다. 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)).
상기 조 플루복사민 유리 염기는 선행문헌, 예를 들어 미국특허 제4,085,225호에 개시된 방법에 따라 제조할 수 있으며, 통상 약 80 내지 95%의 HPLC 순도를 갖는 오일 상으로 얻어진다. 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%.
상기 타르타르산 수용액은 타르타르산을 물에 용해시켜 얻어질 수 있으며, 이때 타르타르산의 사용량은 조 플루복사민 유리 염기 1몰에 대하여 0.9 내지 1.2 몰, 바람직하게는 0.98 내지 1.2 몰의 양으로 사용될 수 있다. 또한, 상기 타르타르산 수용액의 제조시 사용되는 물의 양은 크게 제한되는 것은 아니며, 예를 들어 타르타르산 1 중량부에 대하여 1∼4 중량부의 범위로 사용될 수 있다. 상기 타르타르산은 L-(+)-타르타르산, D-(-)-타르타르산, DL-타르타르산 모두를 사용할 수 있으며, 수율 및 순도의 측면에서 L-(+)-타르타르산이 특히 바람직하게 사용될 수 있다.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. In addition, 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.
단계(a)에서 사용되는 상기 수-혼화성 유기용매는 아세톤, 아세토니트릴, 테트라히드로퓨란 등일 수 있으며, 바람직하게는 아세톤일 수 있다. The water-miscible organic solvent used in step (a) may be acetone, acetonitrile, tetrahydrofuran, etc., preferably acetone.
상기한 바와 같이, 단계(a)에서 얻어진 반응 혼합물은 이어지는 단계(b)의 공정에 직접 사용될 수 있다. 한편, 공업적 규모의 대량생산으로 규모를 증대할 경우, 단계(a)의 반응 혼합물에 존재하는 침전물이 미세 입자의 형태로 생성되어 이어지는 단계(b)의 여과가 장시간이 소요될 수 있다. 그러나, 단계(a)의 반응 혼합물을 가온하여 일정 시간 동안 교반한 다음 실온으로 냉각할 경우, 보다 큰 입자의 형태가 얻어짐으로써, 이어지는 여과를 간단히 수행할 수 있다는 것이 발견되었다. 따라서, 본 발명의 일 구현예에서, 단계(a)는 조 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시켜 얻어진 반응 혼합물을 40∼45 ℃에서 30분 내지 2 시간 동안 교반한 다음, 실온에서 30분 내지 1 시간 동안 교반하는 공정을 추가로 포함할 수 있다. As mentioned above, the reaction mixture obtained in step (a) can be used directly in the process of step (b). On the other hand, when the scale is increased by mass production on an industrial scale, 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. However, it has been found that when the reaction mixture of step (a) is warmed up and stirred for a period of time and then cooled to room temperature, larger morphology is obtained, so that subsequent filtration can be carried out simply. Therefore, in one embodiment of the present invention, 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.
본 발명의 정제방법은 플루복사민의 타르타르산염을 얻는 공정 즉, 단계(b)를 포함한다. 단계(b)는 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 건조함으로써 플루복사민의 타르타르산염을 단리할 수 있으며; 또한 선택적으로 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 단계(a)에서 사용된 수-혼화성 유기용매 중에서 슬러리화하고(즉, 유기용매 중에 분산시키고), 얻어진 슬러리를 여과한 다음, 얻어진 고체를 건조함으로써 플루복사민의 타르타르산염을 단리할 수 있다. 상기와 같이 슬러리화 공정을 경유할 경우, 더욱 고순도의 플루복사민 타르타르산염을 얻을 수 있는 장점이 있다.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. When passing through the slurrying process as described above, there is an advantage to obtain a higher purity fluvoxamine tartarate.
본 발명의 정제방법은 플루복사민의 타르타르산염을 플루복사민 자유 염기로 전환하는 단계 즉, 단계(c)를 포함한다. 단계(c)는 단계(b)에서 얻어진 플루복사민의 타르타르산염을 수산화나트륨 수용액과 수-비혼화성 유기용매 중에서 반응시킴으로써 수행될 수 있다. 상기 수-비혼화성 유기용매는 에틸 아세테이트, 디클로로메탄, 디에틸 에테르 등일 수 있으며, 바람직하게는 에틸 아세테이트일 수 있다.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.
본 발명의 정제방법은 또한 얻어진 플루복사민 자유 염기를 단리하는 공정 즉, 단계(d)를 포함한다. 단계(d)는 단계(c)에서 얻어진 반응 혼합물로부터 유기층을 분리한 후, 분리된 유기층을 농축함으로써 수행될 수 있다. 상기 농축에 의해 얻어진 생성물(즉, 정제된 플루복사민 자유 염기)는 고순도 즉, 약 99.5% 이상의 HPLC 순도를 갖는다. 얻어진 생성물은 고순도의 플루복사민 말레이트의 제조에 직접 즉, in situ로 사용될 수 있다.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) has high purity, ie, HPLC purity of at least about 99.5%. The product obtained can be used directly, ie in situ, for the production of high purity fluvoxamine maleate.
따라서, 본 발명은 상기 정제공정을 포함한 플루복사민 말레이트의 제조방법을 포함한다. 상기 정제공정으로부터 얻어진 플루복사민 자유 염기는 공지의 방법, 예를 들어 미국특허 제4,085,225호, 미국특허 제6,433,225호 등에 개시된 말레이트염 전환 방법에 따라 수행될 수 있다. Therefore, 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.
그러나, 본 발명에 따라 정제공정을 수행하여 얻어진 플루복사민 자유 염기는 유기용매를 사용한 재결정 공정을 필요로 하지 않으며, 나아가 물 중에서의 재결정 공정도 수행하지 않고 간단하게 고순도의 플루복사민 말레이트를 제조할 수 있다. However, 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.
따라서, 본 발명의 일 구현예에서, (p) 상기 정제방법에 따라 플루복사민 유리 염기를 얻는 단계; (q) 단계(p)에서 얻어진 플루복사민 유리 염기를 말레인산과 물 중에서 반응시키는 단계; 및 (r) 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민 말레이트를 얻는 단계를 포함하는, 플루복사민 말레이트의 제조방법이 제공된다. Therefore, in one embodiment of the present invention, (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.
단계(r)은 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 5∼10 ℃의 물로 세척한 후, 건조함으로써 바람직하게 수행될 수 있다.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.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.
실시예Example
하기 실시예에서 출발물질로 사용된 조(crude) 플루복사민 유리 염기는 미국특허 제4,085,225호에 개시된 방법(실시예 6)에 따라 제조하였다. 즉, 디메틸포름아미드(12.5 L)에 5-메톡시-4'-트리플루오로메틸발레로페논 옥심(5.0 mol, 1.3 kg), 2-클로로에틸아민 염산염(5.2 mol, 0.6 kg), 및 수산화칼륨(0.7 kg)을 10 ℃에서 차례로 교반하면서 가하였다. 반응 혼합물을 실온에서 2일 동안 교반한 후, 진공 농축하여 디메틸포름아미드를 제거하였다. 얻어진 잔사를 물에 넣고, pH 3이 될 때까지 2N 염산을 가하였다. 에테르를 이용하여 잔류하는 옥심을 제거한 후, 물층에 2N 수산화나트륨을 가하였다. 얻어진 용액을 에테르로 3회 추출하고, 유기층을 합하여 5% 중탄산나트륨으로 세척한 후, 소듐 설페이트 상에서 건조한 다음, 진공 농축하여 오일 상의 조 플루복사민 유리 염기(1.12 kg, 수율 75%)를 얻었다 (HPLC 순도: 81.9%).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. After removing the remaining oxime using ether, 2N sodium hydroxide was added to the water layer. The resulting solution was extracted three times with ether, the combined organic layers washed with 5% sodium bicarbonate, dried over sodium sulphate and concentrated in vacuo to give crude fluvoxamine free base (1.12 kg, yield 75%) in oil ( HPLC purity: 81.9%).
실시예 1Example 1
단계 1: 플루복사민 L-타르트레이트의 제조Step 1: Preparation of Fluvoxamine L-Tartrate
조 플루복사민 유리 염기(122g, 0.385mol)를 아세톤(1,933g)에 용해시켰다. 다른 용기에 정제수(86g)에 L-(+)-타르타르산(57.7g, 0.385mol)을 용해시켜 얻어진 용액을 상기 조 플루복사민 유리 염기의 아세톤 용액에 가하였다. 반응액을 약 42℃로 가온하여 1시간 동안 교반한 다음, 실온에서 1시간 동안 추가로 교반하여 침전을 생성시켰다. 반응 혼합물을 여과하고, 얻어진 고체를 아세톤(412g)으로 세척하였다. 얻어진 고체를 아세톤(995g)에 넣고 실온에서 1시간 슬러리화한 후, 여과하고, 얻어진 고체를 아세톤(212g)으로 세척한 다음, 약 40℃에서 진공 건조시켜 플루복사민 L-타르트레이트 156.5g을 얻었다(수율: 87%, HPLC 순도: 98.9%). Crude fluvoxamine free base (122 g, 0.385 mol) was dissolved in acetone (1,933 g). In another vessel, a solution obtained by dissolving L-(+)-tartaric acid (57.7 g, 0.385 mol) in purified water (86 g) was added to the acetone solution of the crude fluvoxamine free base. The reaction solution was warmed to about 42 ° C. and stirred for 1 hour, followed by further stirring at room temperature for 1 hour to form a precipitate. The reaction mixture was filtered and the solid obtained was washed with acetone (412 g). The obtained solid was put into acetone (995 g), slurried at room temperature for 1 hour, filtered, the obtained solid was washed with acetone (212 g), and dried in vacuo at about 40 ° C. to give 156.5 g of fluvoxamine L-tartrate. Obtained (yield: 87%, HPLC purity: 98.9%).
단계 2: 플루복사민 유리 염기의 제조Step 2: Preparation of Fluvoxamine Free Base
상기에서 얻어진 플루복사민 L-타르트레이트(112g, 0.239mol)을 에틸 아세테이트(404g)에 슬러리화한 후, 수산화나트륨(28.7g)을 물(207kg) 용해시켜 얻어진 용액을 가하고, 1시간 동안 교반하였다. 유기층을 취하여 정제수로 1회 세척한 다음, 농축하여 플루복사민 유리 염기 72.2g을 얻었다(수율: 95%, HPLC 순도: 99.5%).The fluvoxamine L-tartrate (112g, 0.239mol) obtained above was slurried in ethyl acetate (404g), and then a solution obtained by dissolving sodium hydroxide (28.7g) in water (207kg) was added thereto, followed by stirring for 1 hour. It was. The organic layer was taken up, washed once with purified water, and concentrated to give 72.2 g of fluvoxamine free base (yield: 95%, HPLC purity: 99.5%).
단계 3: 플루복사민 플루복사민 말레이트의 제조Step 3: Preparation of Fluvoxamine Fluvoxamine Maleate
정제수(493g)에 말레인산(33.3g 0.287mol)을 용해시켜 얻어진 용액을 상기 농축된 플루복사민 유리 염기에 첨가하고 2시간 실온에서 교반하였다. 생성된 고체를 여과하고, 약 10℃로 냉각한 정제수(34g)로 세척한 다음, 약 30℃ 열풍순환 건조기로 건조하여 플루복사민 말레이트 93.5g을 얻었다(수율: 95%, HPLC 순도: 99.9%).A solution obtained by dissolving maleic acid (33.3 g 0.287 mol) in purified water (493 g) was added to the concentrated fluvoxamine free base and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with purified water (34 g) cooled to about 10 ° C., and then dried with a hot air circulation dryer (about 30 ° C.) to obtain 93.5 g of fluvoxamine maleate (yield: 95%, HPLC purity: 99.9). %).
실시예 2Example 2
L-(+)-타르타르산 대신 D-(-)-타르타르산(57.7g, 0.385mol)을 사용한 것을 제외하고는, 실시예 1의 단계 1과 동일한 방법으로 반응을 수행하여 플루복사민 D-타르트레이트 144.3g을 얻었다(수율: 80%, HPLC 순도: 98.1%). 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%).
또한, 상기에서 얻어진 플루복사민 D-타르트레이트(112g, 0.239mol)을 사용하여 실시예 1의 단계 2 및 3과 동일한 방법으로 반응을 수행하여 플루복사민 유리 염기 69.6g(수율: 91.5%, HPLC 순도: 98.8%) 및 플루복사민 말레이트 90.3g(수율: 91.6%, HPLC 순도: 99.1%)을 얻었다.Further, by using the fluvoxamine D-tartrate (112g, 0.239mol) obtained above in the same manner as in steps 2 and 3 of Example 1 to 69.6g of fluvoxamine free base (yield: 91.5%, HPLC purity: 98.8%) and 90.3 g of fluvoxamine maleate (yield: 91.6%, HPLC purity: 99.1%) were obtained.
실시예 3Example 3
L-(+)-타르타르산 대신 DL-타르타르산(57.7g, 0.385mol)을 사용한 것을 제외하고는, 실시예 1의 단계 1과 동일한 방법으로 반응을 수행하여 플루복사민 DL-타르트레이트 155.1g을 얻었다(수율: 86%, HPLC 순도: 98.6%). 155.1 g of fluvoxamine DL-tartrate was obtained by the same method as Step 1 of Example 1, except that DL-tartaric acid (57.7 g, 0.385 mol) was used instead of L-(+)-tartaric acid. (Yield 86%, HPLC Purity: 98.6%).
또한, 상기에서 얻어진 플루복사민 DL-타르트레이트(112g, 0.239mol)을 사용하여 실시예 1의 단계 2 및 3과 동일한 방법으로 반응을 수행하여 플루복사민 유리 염기 68.8g(수율: 90.5%, HPLC 순도: 99.0%) 및 플루복사민 말레이트 91.9g(수율: 93.2%, HPLC 순도: 99.6%)을 얻었다.Further, by using the fluvoxamine DL-tartrate (112g, 0.239mol) obtained above in the same manner as in Steps 2 and 3 of Example 1, 68.8g of fluvoxamine free base (yield: 90.5%, HPLC purity: 99.0%) and 91.9 g of fluvoxamine maleate (yield: 93.2%, HPLC purity: 99.6%).
비교예 1. 미국특허 제4,085,225호의 실시예 6에 따라 제조Comparative Example 1. Prepared according to Example 6 of US Pat. No. 4,085,225.
디메틸포름아미드(12.5 ml)에 5-메톡시-4'-트리플루오로메틸발레로페논 옥심(5.0 mmol, 1.3 g), 2-클로로에틸아민 염산염(5.2 mmol, 0.60 g), 및 수산화칼륨(0.7 g)을 10 ℃에서 차례로 교반하면서 가하였다. 반응 혼합물을 실온에서 2일 동안 교반한 후, 진공 농축하여 디메틸포름아미드를 제거하였다. 얻어진 잔사를 물에 넣고, pH 3이 될 때까지 2N 염산을 가하였다. 에테르를 이용하여 잔류하는 옥심을 제거한 후, 물층에 2N 수산화나트륨을 가하였다. 얻어진 용액을 에테르로 3회 추출하고, 유기층을 합하여 5% 중탄산나트륨으로 세척한 후, 소듐 설페이트 상에서 건조한 다음, 진공 농축하였다. 얻어진 잔사를 무수 에탄올에 용해시키고, 동일 당량(equimolar)의 말레인산을 가하였다. 맑은 용액이 얻어질 때까지 반응 혼합물을 환류 교반한 다음, 진공 농축하여 에탄올을 제거하였다. 얻어진 잔사를 아세토니트릴로부터 재결정하여 플루복사민 말레이트 1.3g을 얻었다(수율: 63.4%, HPLC 순도: 97.3%)를 얻었다Dimethylformamide (12.5 ml) in 5-methoxy-4'-trifluoromethylvalerophenone oxime (5.0 mmol, 1.3 g), 2-chloroethylamine hydrochloride (5.2 mmol, 0.60 g), and potassium hydroxide ( 0.7 g) 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. After removing the remaining oxime using ether, 2N sodium hydroxide was added to the water layer. The resulting solution was extracted three times with ether, the combined organic layers were washed with 5% sodium bicarbonate, dried over sodium sulphate and then concentrated in vacuo. The obtained residue was dissolved in anhydrous ethanol and the same equivalent maleic acid was added. The reaction mixture was stirred at reflux until a clear solution was obtained and then concentrated in vacuo to remove ethanol. The obtained residue was recrystallized from acetonitrile to obtain 1.3 g of fluvoxamine maleate (yield: 63.4%, HPLC purity: 97.3%).
비교예 2.Comparative Example 2.
정제수(493g)에 말레인산(33.3g 0.287mol)을 용해시켜 얻어진 용액을 조 플루복사민 유리 염기(72.2g, 0.227mol)에 첨가하고 2시간 실온에서 교반하였다. 생성된 고체를 여과하고, 약 10℃로 냉각한 정제수(34g)로 세척한 다음, 약 30℃ 열풍순환 건조기로 건조하여 플루복사민 말레이트 91.1g을 얻었다(수율: 92.4%, HPLC 순도: 94.7%).The solution obtained by dissolving maleic acid (33.3 g 0.287 mol) in purified water (493 g) was added to the crude fluvoxamine free base (72.2 g, 0.227 mol) and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with purified water (34 g) cooled to about 10 ° C., and then dried with a hot air circulation dryer (about 30 ° C.) to obtain 91.1 g of fluvoxamine maleate (yield: 92.4%, HPLC purity: 94.7). %).
Claims (7)
- 하기 단계를 포함하는 플루복사민 유리 염기의 정제방법:Method for purifying fluvoxamine free base comprising the following steps:(a) 조(crude) 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시키는 단계;(a) reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent;(b) (i) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻거나, 혹은 (b) (i) filtering the reaction mixture of step (a), and then drying the obtained solid to obtain tartarate of fluvoxamine, or(ii) 단계(a)의 반응 혼합물을 여과한 다음, 얻어진 고체를 단계(a)에서 사용된 수-혼화성 유기용매 중에서 슬러리화하고, 얻어진 슬러리를 여과한 다음, 얻어진 고체를 건조하여 플루복사민의 타르타르산염을 얻는 단계;(ii) filtering the reaction mixture of step (a), and then slurrying the obtained solid in the water-miscible organic solvent used in step (a), filtering the obtained slurry, and then drying the obtained solid to influenza radiation Obtaining a tartarate of min;(c) 단계(b)에서 얻어진 플루복사민의 타르타르산염을 수산화나트륨 수용액과 수-비혼화성 유기용매 중에서 반응시키는 단계; 및(c) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent; And(d) 단계(c)에서 얻어진 반응 혼합물로부터 유기층을 분리한 후, 분리된 유기층을 농축하여 플루복사민 유리염기를 얻는 단계.(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.
- 제1항에 있어서, 상기 타르타르산이 L-(+)-타르타르산인 것을 특징으로 하는 정제방법.The method of claim 1, wherein the tartaric acid is L-(+)-tartaric acid.
- 제1항에 있어서, 단계(a)에서 사용되는 상기 수-혼화성 유기용매가 아세톤인 것을 특징으로 하는 정제방법.The process according to claim 1, wherein the water-miscible organic solvent used in step (a) is acetone.
- 제1항에 있어서, 단계(a)가 조 플루복사민 유리 염기를 타르타르산 수용액과 수-혼화성 유기용매 중에서 반응시켜 얻어진 반응 혼합물을 40∼45 ℃에서 30분 내지 2 시간 동안 교반한 다음, 실온에서 30분 내지 1 시간 동안 교반하는 공정을 추가로 포함하는 것을 특징으로 하는 정제방법.The reaction mixture of claim 1, wherein step (a) is a reaction mixture obtained by reacting the crude fluvoxamine free base in an aqueous solution of tartaric acid in a water-miscible organic solvent, stirred at 40-45 ° C. for 30 minutes to 2 hours, and then Purifying method further comprises the step of stirring for 30 minutes to 1 hour.
- 제1항에 있어서, 단계(c)에서 사용되는 상기 수-비혼화성 유기용매가 에틸 아세테이트인 것을 특징으로 하는 정제방법.The process according to claim 1, wherein the water-immiscible organic solvent used in step (c) is ethyl acetate.
- (p) 제1항 내지 제5항 중 어느 한 항에 따른 정제방법에 따라 플루복사민 유리 염기를 얻는 단계; (q) 단계(p)에서 얻어진 플루복사민 유리 염기를 말레인산과 물 중에서 반응시키는 단계; 및 (r) 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 건조하여 플루복사민 말레이트를 얻는 단계를 포함하는, 플루복사민 말레이트의 제조방법.(p) obtaining fluvoxamine free base according to the purification method according to any one of claims 1 to 5; (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.
- 제6항에 있어서, 단계(r)이 단계(q)에서 얻어진 반응 혼합물을 여과한 다음, 얻어진 고체를 5∼10 ℃의 물로 세척한 후, 건조함으로써 수행되는 것을 특징으로 하는 플루복사민 말레이트의 제조방법.The fluvoxamine malate according to claim 6, wherein step (r) is carried out by filtration of the reaction mixture obtained in step (q), and then washing the obtained solid with water at 5 to 10 DEG C, followed by drying. Manufacturing method.
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