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 PDF

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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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step
fluvoxamine
method
free base
obtained
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PCT/KR2013/007647
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French (fr)
Korean (ko)
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전성현
유혜심
성진의
서경재
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주식회사 에스텍파마
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/14Separation; Purification; Stabilisation; Use of additives

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

Production method of the purification method of fluvoxamine and a high purity free base fluvoxamine maleate using the same.

The present invention relates to a method for purifying the flu copy min free base and the method for producing a high purity fluvoxamine maleate using the same, which comprises the conversion fluvoxamine free base with fluvoxamine tartrate.

Fluvoxamine maleate (fluvoxamine maleate) is to a compound having the structure of formula (1), used by adjusting the concentration of serotonin through 5HT4- receptor antagonistic action and selective serotonin reuptake inhibitory activity is useful in the treatment of depression and major depressive disorder do.

<Formula 1>

Figure PCTKR2013007647-appb-I000001

U.S. Patent No. 4,085,225 discloses a fluorene discloses a copy min maleate and their preparation. U.S. Patent No. 4,085,225 discloses 5-methoxy-4'-tree and discloses a manufacturing method comprising a fluoro-methyl ballet reacting the benzophenone oxime and 2-chloro-ethylamine hydrochloride, the product that is finally obtained, fluorenyl copy Min maleate is purified by recrystallization from acetonitrile. However, by using an organic solvent such as acetonitrile in the final step, there is a problem of the residual solvent, in particular fluvoxamine end the purity of the rate is relatively low (HPLC purity: about 97.3%), there is a problem.

U.S. Patent No. 6,433,225 discloses a method for producing an improved flu copy seeds. Involves reaction in an immiscible organic solvent, said U.S. Patent No. 6,433,225 discloses a number of under 5-methoxy-4'-trifluoromethyl acetophenone oxime and 2-chloro-ethylamine hydrochloride in the presence of a base with methyl ballet. Fluvoxamine maleate obtained from the final stage performs a purification step through a number of unit operations of filtration, toluene was washed, dried and recrystallized with water, filtered, washed with cold water, and drying. However, there is no purification step in a reaction medium there is a limit to the final compound by purifying by recrystallization from water, a number of tablets of a flexible organic material generated in the reaction difficult to obtain a high purity of fluvoxamine maleate.

The present inventors have conducted various studies to develop a method of manufacturing an organic flexible material and residual solvent is fluvoxamine maleate having essentially a high purity that is, more than 99% HPLC purity removed. The inventors have discovered that the purity of fluvoxamine maleate has a decisive influence on the purity of fluvoxamine free base used in the maleate salt form. In particular, the inventors have found that crude (crude) fluvoxamine free base the flu copy seeds tartrate (fluvoxamine tartrate) after switching, the back fluvoxamine When making the transition to the free base, fluorenyl purity of copy min free base that was found that the significantly increased, it was found that fluorene could be produced copy Num maleate having at least 99% HPLC purity when to switch it to the maleate salt form.

Accordingly, an object of the present invention is to provide a purification method of fluvoxamine free base containing the transition to flu copy seeds tartrate.

Further, an object of the present invention is to provide a method for producing a high purity of fluvoxamine maleate flu from copy min free base obtained from the above purification method.

According to one aspect of the invention, a method for purification of the fluorene copy min free base comprising the step it is provided:

(A) crude (crude) of fluvoxamine free base and tartaric acid can be an aqueous solution - reacting in a water-miscible organic solvent;

(B) filtering the reaction mixture of step (i) (a), and then obtains a copy seeds tartrate flu and dried to obtain a solid, or, or (ii) filtering the reaction mixture of step (a), and then the solid thus obtained the number used in step (a) - a step horn slurry from the chemical conversion of organic solvation, and the slurry thus obtained was filtered to get the next, copy seeds tartrate flu and dried to obtain a solid;

(C) (b) can be obtained with Flu copy seeds tartrate aqueous solution of sodium hydroxide in step-reacting from immiscible organic solvent; And

(D) step (c) and then the organic layer was separated from the reaction mixture obtained in the concentration of the separated organic layer to obtain the free base fluvoxamine.

In the method according to the present invention, the tartaric acid is preferably L - may be tartaric acid, the number used in the steps (a) - - (+) water-miscible organic solvent may be preferably from acetone. Step (a) is a crude fluvoxamine can and the free base of tartaric acid aqueous solution to a reaction mixture obtained by reacting the horn from the chemical conversion of organic solvent and stirred at 40~45 ℃ for 30 minutes to 2 hours, 30 minutes to 1 hour at room temperature during may further comprise the step of stirring. In addition, the number used in the steps (c) - immiscible organic solvent may be preferably ethyl acetate.

According to another aspect of the invention, to obtain a copy min free base fluorene according to the purification process; (Q) a step of fluvoxamine the free base obtained in step (p) from the reaction of maleic acid and water; And (r) by filtering the reaction mixture obtained in step (q), and then, the production method of drying the solid containing a step for obtaining fluvoxamine maleate, fluvoxamine maleate thus obtained is provided.

It said step (r) may be preferably carried out by washed by filtering the reaction mixture obtained in step (q), then the resulting solid with water of 5~10 ℃, drying.

According to the present invention, crude (crude) fluvoxamine free base the flu copy seeds tartrate (fluvoxamine tartrate) after switching, the back fluvoxamine When making the transition to the free base, fluorenyl purity of copy min free base It has been found to significantly increase. In addition, it has been found that when switching fluvoxamine free base obtained by the purification method to a maleate salt form of fluvoxamine maleate having at least 99% HPLC purity can be produced. In addition, the production method of fluvoxamine maleate according to the present invention is an organic solvent (e.g., acetonitrile), or with water without performing a recrystallization process, a simple cold water (e.g. water for 5~10 ℃) washing can be produced fluvoxamine maleate in high purity by a.

The present invention provides a method for purifying the flu copy min free base, comprising:

(A) crude (crude) of fluvoxamine free base and tartaric acid can be an aqueous solution - reacting in a water-miscible organic solvent;

(B) filtering the reaction mixture of step (i) (a), and then obtains a copy seeds tartrate flu and dried to obtain a solid, or, or (ii) filtering the reaction mixture of step (a), and then the solid thus obtained the number used in step (a) - a step horn slurry from the chemical conversion of organic solvation, and the slurry thus obtained was filtered to get the next, copy seeds tartrate flu and dried to obtain a solid;

(C) (b) can be obtained with Flu copy seeds tartrate aqueous solution of sodium hydroxide in step-reacting from immiscible organic solvent; And

(D) step (c) and then the organic layer was separated from the reaction mixture obtained in the concentration of the separated organic layer to obtain the free base fluvoxamine.

Purification method of the invention involves the conversion of the copy seeds tartrate flu crude fluvoxamine free base. Flu copy seeds tartrate (fluvoxamine tartrate) is high and easy access by recrystallization method, because the solubility in organic solvents such as acetone, ethyl acetate, ether, methanol, ethanol, isopropyl alcohol is very low can be obtained in high yield and high purity is. In particular, oil-type of fluvoxamine free base is purified by column chromatography (column chromatography), but a method to purify different than that, fluorenyl copy seeds tartrate is because it is solid, not oily, inefficient purified by column chromatography on a target production It can be easily obtained without the use of.

The purification method of the invention is crude (crude) fluvoxamine glass to be as tartaric acid aqueous solution of a base - a step that is, Step (a)] is reacted in a water-miscible organic solvent.

The crude fluvoxamine free base is obtained in the oil phase with the preceding literature, for example, United States can be prepared according to the process disclosed in Patent No. 4,085,225, typically HPLC purity of about 80 to 95%.

The tartaric acid solution can be obtained by dissolving tartaric acid in water, wherein the amount of tartaric acid can be used in an amount of 0.9 to 1.2 mol, preferably 0.98 to 1.2 mol per 1 mol of the free base crude fluvoxamine. Also, not necessarily the amount of water that is largely limited to be used in the preparation of the aqueous solution of tartaric acid can be used, for example, to 1 to 4 parts by weight of the range with respect to 1 part by weight of tartaric acid. The tartaric acid is L - (+) - tartaric acid, D - (-) - tartaric acid, DL- tartaric acid can be used both, in terms of yield and purity of L-tartaric acid can be used is particularly preferably - (+).

The number used in the steps (a) - miscible organic solvent may be acetone, acetonitrile, and the like tetrahydrofuran, preferably acetone.

As described above, the reaction mixture obtained in step (a) may be used directly in process step (b) leading. On the other hand, the filtration of industrial scale if increasing the scale of mass production, the method comprising the steps of: (a) (b) leading to the generation of precipitates in the form of fine particles present in the reaction mixture may take a long time. However, when cooled to room temperature and then stirred for a period of time by heating the reaction mixture of step (a), by being in the form of larger particles obtained, it has been found that can easily perform the subsequent filtering. Thus, in one embodiment of the invention, step (a) is a crude fluvoxamine free base an aqueous solution of tartaric acid and water-stirring for 30 minutes the reaction mixture obtained by reacting the horn from the chemical conversion of organic solvent in 40~45 ℃ to 2 hours. and then, it may further comprise the step of stirring for 30 minutes to 1 hour at room temperature.

Purification method of the invention includes a process that is, to obtain a copy flu seeds tartrate (b). Step (b) filtering the reaction mixture of step (a) then, by drying the obtained solid fluorene can be isolated copy seeds and tartrate; Also optionally, filtering the reaction mixture of step (a), and then, the number of using the solid obtained in step (a) - slurry in a water-miscible organic solvent screen (that is, dispersed in an organic solvent and), the slurry obtained was filtered by then, it dried to obtain a solid fluorene can be isolated copy seeds tartrate. When via a slurry process as described above, there is an advantage to gain fluvoxamine tartrate of higher purity.

Purification method of the present invention comprises the steps i. E., Step (c) to switch the flu copy seeds tartrate as fluvoxamine free base. Step (c) to step (b) can be obtained with Flu copy aqueous solution of sodium hydroxide in the seeds tartrate-incompatible can be performed by reaction in an organic solvent Mars. The water-immiscible organic solvent and the like, diethyl ether, ethyl acetate, dichloromethane, and may preferably be ethyl acetate.

Purification method of the present invention also comprise a step of isolation of the free base obtained fluvoxamine i.e., step (d). Step (d), after the organic layer was separated from the reaction mixture obtained in step (c), it can be carried out by concentrating the separated organic layer. The product (i.e., the purified fluvoxamine free base) obtained by the concentrate has a high purity that is, HPLC purity of at least about 99.5%. The obtained product can be used directly i.e., in situ in the preparation of high purity fluvoxamine maleate.

Accordingly, the present invention includes a method of fluvoxamine maleate, including the purification step. The tablets fluvoxamine free base obtained from the process is a known method, for example, it is performed according to the maleate salt conversion method disclosed in U.S. Patent No. 4,085,225, U.S. Patent No. 6,433,225.

However, fluvoxamine free base is obtained by performing the purification step according to the present invention does not require any re-crystallization step using an organic solvent, and further the fluvoxamine maleate simply a high purity without also performing the recrystallization process in water It can be prepared.

Thus, in one embodiment of the invention, (p) to obtain the free base copy min flu according to the purification process; (Q) a step of fluvoxamine the free base obtained in step (p) from the reaction of maleic acid and water; And (r) by filtering the reaction mixture obtained in step (q), and then, the production method of drying the solid containing a step for obtaining fluvoxamine maleate, fluvoxamine maleate thus obtained is provided.

Step (r) may be preferably carried out by washed by filtering the reaction mixture obtained in step (q), then the resulting solid with water of 5~10 ℃, drying.

Will be described below in more detail the present invention through the embodiments. However, these examples are intended to illustrate the invention, but is not the scope of the present invention is limited to these Examples.

Example

The following Examples in the crude (crude) fluvoxamine free base as a starting material was prepared according to the process disclosed in U.S. Patent No. 4,085,225 (Example 6). That is, benzophenone oxime (5.0 mol, 1.3 kg), 2- chloroethyl amine hydrochloride (5.2 mol, 0.6 kg), and hydroxide 5-Methoxy-4'-trifluoromethyl-dimethylformamide (12.5 L) with methyl ballet potassium (0.7 kg) was added with stirring and then at 10 ℃. After stirring for 2 days the reaction mixture at room temperature, and vacuum concentrated to remove the dimethylformamide. The obtained residue was put into water, and a 2N hydrochloric acid until pH 3. After removing the remaining oxime, using the ether, it was added 2N sodium hydroxide in aqueous. Extracted with three of the resulting solution with ether, then the combined organic layers were washed with 5% sodium bicarbonate, dried over sodium sulfate and then concentrated in vacuo to give the crude as an oil fluvoxamine free base (1.12 kg, 75% yield) ( HPLC purity: 81.9%).

Example 1

Step 1: Preparation of fluvoxamine L- tartrate

The crude free base fluvoxamine (122g, 0.385mol) was dissolved in acetone (1,933g). (+) - - L in purified water (86g) in another container a solution obtained by dissolving tartaric acid (57.7g, 0.385mol) was added to the crude flu acetone solution of the free base copy min. The reaction mixture was stirred by heating to about 42 ℃ for 1 hour then allowed to precipitate with stirring for a further 1 hour at room temperature. The reaction mixture was filtered, washing the resulting solid with acetone (412g). Insert the resulting solid in acetone (995g) was slurried for 1 hour at room temperature, filtered, and vacuum-dried to obtain a solid in the washing with acetone (212g), and then, about 40 ℃ flu copy min L- tartrate 156.5g It was obtained (yield: 87%, HPLC purity: 98.9%).

Step 2: Preparation of fluorene copy min free base

Flu copy obtained from the Nu L- tartrate (112g, 0.239mol) was added to a solution obtained by dissolving ethyl acetate and then slurried in (404g), water (207kg) of sodium hydroxide (28.7g), and stirred for 1 hour It was. By taking the organic layer was washed once with distilled water and then concentrated to give the free base fluvoxamine 72.2g (yield: 95%, HPLC purity: 99.5%).

Step 3: Preparation of fluorene copy min fluvoxamine maleate

Purified water (493g) of maleic acid (33.3g 0.287mol) was dissolved was added to the resulting solution to the concentration of fluvoxamine to the free base, which was stirred at room temperature for 2 hours. The resulting solid was filtered, washed with about 10 ℃ a purified water (34g) with cooling, and then dried at about 30 ℃ hot air circulating drier to obtain a fluvoxamine maleate 93.5g (yield: 95%, HPLC purity: 99.9 %).

Example 2

L - (+) - tartaric acid instead of D - (-) - tartaric acid and is to perform the reaction in the same manner as in Step 1 of Example 1, except for using (57.7g, 0.385mol) fluvoxamine D- tartrate to give a 144.3g (yield: 80%, HPLC purity: 98.1%).

Furthermore, flu copy obtained from the Nu D- tartrate (112g, 0.239mol) by an embodiment of steps 1 and 2 and 3 carry out the reaction in the same manner by fluvoxamine free base 69.6g (Yield used: 91.5%, HPLC purity: 98.8%), and fluvoxamine maleate 90.3g (yield: 91.6%, HPLC purity: to obtain a 99.1%).

Example 3

L - (+) - tartaric acid instead, except that the DL- tartaric acid (57.7g, 0.385mol) is carried out by performing a reaction in the same manner as in Step 1 of Example 1, fluvoxamine DL- tartrate to give the 155.1g (yield: 86%, HPLC purity: 98.6%).

Further, the copy obtained in the above-mentioned fluorene min DL- tartrate (112g, 0.239mol) by an embodiment of steps 1 and 2 and 3 carry out the reaction in the same manner by fluvoxamine free base 68.8g (Yield used: 90.5%, HPLC purity: 99.0%), and fluvoxamine maleate 91.9g (yield: 93.2%, HPLC purity: 99.6%) was obtained.

Comparative Example 1 prepared according to Example 6 of U.S. Patent No. 4,085,225

Dimethylformamide in (12.5 ml) ballet methyl 5-methoxy-4'-trifluoromethyl acetophenone oxime (5.0 mmol, 1.3 g), 2- chloro-ethylamine hydrochloride (5.2 mmol, 0.60 g), and potassium ( the 0.7 g) was added with stirring and then at 10 ℃. After stirring for 2 days the reaction mixture at room temperature, and vacuum concentrated to remove the dimethylformamide. The obtained residue was put into water, and a 2N hydrochloric acid until pH 3. After removing the remaining oxime, using the ether, it was added 2N sodium hydroxide in aqueous. Extracted three times with ether and the resulting solution, and then the combined organic layers were washed with 5% sodium bicarbonate, dried and concentrated, and then vacuum over sodium sulfate. The resulting residue was dissolved in absolute ethanol, it was added to the maleic acid in the same equivalent weight (equimolar). A clear solution at reflux the reaction mixture was stirred until the obtained was removed, and then ethanol, and vacuum concentrated. The resulting residue was recrystallized from acetonitrile to give the fluvoxamine maleate 1.3g (yield: 63.4%, HPLC purity: 97.3%) of the

Comparative Example 2.

By dissolving the crude maleic acid (33.3g 0.287mol) in purified water (493g) was added to the resulting solution fluorenyl copy min free base (72.2g, 0.227mol) and stirred at room temperature for 2 hours. The resulting solid was filtered, washed with about 10 ℃ a purified water (34g) with cooling, and then dried at about 30 ℃ hot air circulating drier to obtain a fluvoxamine maleate 91.1g (yield: 92.4%, HPLC purity: 94.7 %).

Claims (7)

  1. Fluvoxamine glass purification method of a base comprising the following steps:
    (A) crude (crude) of fluvoxamine free base and tartaric acid can be an aqueous solution - reacting in a water-miscible organic solvent;
    (B) (i) filtering the reaction mixture of step (a) then, or get a copy seeds tartrate flu and dried to obtain a solid, or
    (Ii) filtering the reaction mixture of step (a), and then, the number of use of the obtained solid in step (a) - a horn slurry from the chemical conversion of organic solvation, and the slurry thus obtained was filtered and then dried, thereby obtaining the solid fluorenyl copy to obtain the seeds tartrate;
    (C) (b) can be obtained with Flu copy seeds tartrate aqueous solution of sodium hydroxide in step-reacting from immiscible organic solvent; And
    (D) step (c) and then the organic layer was separated from the reaction mixture obtained in the concentration of the separated organic layer to obtain the free base fluvoxamine.
  2. The method of claim 1, wherein the tartaric acid is L - tablets wherein the tartaric acid is (+).
  3. The method of claim 1 wherein said number of used in Step (a) - a purification method which is characterized in that the water-miscible organic solvent is acetone.
  4. In the step (a) the crude fluvoxamine free base with a tartaric acid aqueous solution be in the 1-stirring the reaction mixture obtained by reacting the horn from the chemical conversion of organic solvent in 40~45 ℃ for 30 minutes to 2 hours and then at room temperature 30 minutes to 1 purification method characterized in that it comprises an additional step of stirring for hours.
  5. The method of claim 1 wherein said number of used in Step (c) - incompatible purification method, characterized in that the chemical conversion of ethyl acetate to the organic solvent.
  6. (P) the second step to obtain fluvoxamine free base according to the purification process according to any one of items 1 to 5; (Q) a step of fluvoxamine the free base obtained in step (p) from the reaction of maleic acid and water; And (r) by filtering the reaction mixture obtained in step (q), and then dried, thereby obtaining the solid-state method for producing fluvoxamine end step, fluvoxamine maleate containing obtain the rate.
  7. The method of claim 6, wherein step (r) the step (q) The reaction mixture obtained from the filtration, the solid obtained was washed with water of 5~10 ℃, dried fluvoxamine maleate, characterized in that is carried out by the method of manufacture.
PCT/KR2013/007647 2012-08-29 2013-08-27 Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same WO2014035107A1 (en)

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KR900001420B1 (en) * 1983-11-22 1990-03-09 아흐렌스, 포트만 Process for the production of 4-amino -6,7- dimethoxy-2-(4-(furo-2-yl)-p (perazin-1yl) -qinazoline and physiologically compatible salts thereof
KR950000778B1 (en) * 1989-09-28 1995-02-02 이또오 겐지 Optically active benzyl alcohol compound and the use thereof
US6433225B1 (en) * 1999-11-12 2002-08-13 Sun Pharamaceutical Industries, Ltd. Process for the preparation of fluvoxazmine maleate
KR20050043776A (en) * 2001-11-08 2005-05-11 세프라코 아이엔시. Methods for treating depression and other cns disorders using enantiomerically enriched desmethyl- and didesmethyl- metabolites of citalopram

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JP2006225272A (en) * 2005-02-15 2006-08-31 Sumitomo Chemical Co Ltd (r)-n-(3,4-dimethoxybenzyl)-1-phenylethylamine l-tartrate and method of purifying (r)-n-(3,4-dimethoxybenzyl)-1-phenylethylamine using the same
CZ300692B6 (en) * 2006-12-22 2009-07-15 Zentiva, A. S. Solifenacin preparation process
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Publication number Priority date Publication date Assignee Title
KR900001420B1 (en) * 1983-11-22 1990-03-09 아흐렌스, 포트만 Process for the production of 4-amino -6,7- dimethoxy-2-(4-(furo-2-yl)-p (perazin-1yl) -qinazoline and physiologically compatible salts thereof
KR950000778B1 (en) * 1989-09-28 1995-02-02 이또오 겐지 Optically active benzyl alcohol compound and the use thereof
US6433225B1 (en) * 1999-11-12 2002-08-13 Sun Pharamaceutical Industries, Ltd. Process for the preparation of fluvoxazmine maleate
KR20050043776A (en) * 2001-11-08 2005-05-11 세프라코 아이엔시. Methods for treating depression and other cns disorders using enantiomerically enriched desmethyl- and didesmethyl- metabolites of citalopram

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JP6228210B2 (en) 2017-11-08
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