WO2014035107A1

WO2014035107A1 - Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same

Info

Publication number: WO2014035107A1
Application number: PCT/KR2013/007647
Authority: WO
Inventors: 전성현; 유혜심; 성진의; 서경재
Original assignee: 주식회사 에스텍파마
Priority date: 2012-08-29
Filing date: 2013-08-27
Publication date: 2014-03-06
Also published as: KR20140028433A; KR101427221B1; JP2015526507A; CN104703967B; JP6228210B2; CN104703967A

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

Purification method of fluvoxamine free base and preparation method of high purity fluvoxamine maleate using the same

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. 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%).

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.

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.

Accordingly, an object of the present invention is to provide a method for purifying fluvoxamine free base, which comprises converting fluvoxamine to tartarate.

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.

According to one aspect of the invention, there is provided a process for purifying fluvoxamine free base, comprising the following steps:

(a) reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent;

(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) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent; And

(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.

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.

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.

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.

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.

The present invention provides a method for purifying fluvoxamine free base comprising the following steps:

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.

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. 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.

The water-miscible organic solvent used in step (a) may be acetone, acetonitrile, tetrahydrofuran, etc., preferably acetone.

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.

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.

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) 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.

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.

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.

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.

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.

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

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

Step 1: Preparation of Fluvoxamine L-Tartrate

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%).

Step 2: Preparation of Fluvoxamine Free Base

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%).

Step 3: Preparation of Fluvoxamine Fluvoxamine Maleate

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

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%).

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

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%).

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.

Dimethylformamide (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.

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

Method for purifying fluvoxamine free base comprising the following steps:

(a) reacting a crude fluvoxamine free base with an aqueous tartaric acid solution in a water-miscible organic solvent;

(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 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) reacting the tartarate salt of fluvoxamine obtained in step (b) with an aqueous sodium hydroxide solution in a water-immiscible organic solvent; And

(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 method of claim 1, wherein the tartaric acid is L-(+)-tartaric acid.
The process according to claim 1, wherein the water-miscible organic solvent used in step (a) is acetone.
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.
The process according to claim 1, wherein the water-immiscible organic solvent used in step (c) is ethyl acetate.
(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.
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.