KR101451171B1 - Manufacturing method of (Loxoprofen (2S, 1'R, 2'S) trans-alcohol - Google Patents

Abstract

[화학식 2]

[화학식 3]

[화학식 4]

[화학식 5]

[화학식 6]

(상기 화학식 4a, 4b, 5a, 5b, 6a 및 6b에서, R은 탄소수 1 내지 10의 알킬기, 탄소수 3 내지 6의 시클로알킬기 또는 S-에틸락테이트기(S-ethyl lactate)이다.).(2S, 1'R, 2'S) trans-alcohol capable of improving the yield and purity, and more particularly, to a process for preparing a trans-alcohol of the formula -Methyl-D-glucamine or N-ethyl-D-glucamine to obtain a solid phase mixture containing the following formulas (3a) and (3b), the solid phase mixture obtained above is esterified To obtain an ester mixture of the following formulas (4a) and (4b), followed by a reduction reaction of the ester mixture prepared in the above step, followed by column chromatography to obtain a trans-alcohol ester mixture (2S, 1 ' R, 2 ' S) trans-alcohols of formula 5a by reaction with lipase and vinyl acetate, To obtain the ester obtained above and a trans-comprises the step of hydrolyzing the ester alcohol.
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(In the above formulas 4a, 4b, 5a, 5b, 6a and 6b, R is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an S-ethyl lactate group).

Description

Manufacturing method of (Loxoprofen (2S, 1'R, 2'S) trans-alcohol} Loxoprofen (2S,

The present invention relates to the use of Loxopreofen (2S, 1'R, 2'S) trans-alcohol as an active metabolite of Loxoprofen, which is used as anti-inflammatory analgesic, 2'S) trans-alcohol].

[Chemical Formula 1]

Generally, Loxoprofen (2- [4- (2-oxocyclenpentyl) phenyl] propionic acid) is widely used as a propionic acid nonsteroidal anti-inflammatory drug (NSAID) . It is mainly used for chronic joint rheumatism, deformed arthropathy, urinary pain, shoulder joint inflammation, etc., and is also effective for post-operative, post-traumatic and post-operative pain relief.

(2R, 1'R), (2R, 1'S), (2S, 1'S), and , And substantially all of the isomers are contained in a ratio of about 25%.

(2)

Such a loxoprofen is a kind of pro-drug. According to its metabolic pathway, after oral administration of loxoprofen, the cyclopentanone ketone is directly reduced to alcohol by the reduction reaction of the enzyme in the body, And this metabolite is a substantially active substance. It is known that this active substance has a therapeutic effect by inhibiting the biosynthesis of prostaglandin, a pain inducing substance.

Especially, as the cyclopentanone is converted into cyclopentanol, eight isomers are possible. Among them, a cyclosiloxane represented by the following formula (1) in the form of a trans having an orientation of (2S, 1'R, 2'S) Pen (2S, 1'R, 2'S) trans-alcohol is known to have the most potent activity. (Reference:....... .. Jpn J. Inflamm 1982, 2, 263; J. Med Chem 1984, 27, 212; Chem Pharm Bull (Tokyo) 1984, 32, 258; Chem Pharm Bull 1983. , 31, 4319)

[Chemical Formula 1]

Thus, various methods have been proposed to produce the loxoprofen (2S, 1'R, 2'S) trans-alcohol of the formula 1 as the substantially active metabolite of loxoprofen.

In this regard, U.S. Patent No. 4,400,534 discloses a process for the production of the Rocsoprofen (2S, 1'R, 2'S) trans-alcohol of Chemical Formula 1 as shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

According to the above method, the Rocopsoprene was recrystallized several times with ethyl acetate or hexane to obtain erythro (2S, 1'R) -Loxoprofen and (2R, 1'S) The mixture (A) was obtained and subjected to a coupling reaction with (S) -methylbenzylamine as a chiral resolving agent to prepare a diastereomer of 1-α-phenylamide derivative, (2S, 1'R) -phenylamide derivative (B) using column chromatography. (2S, 1'R) -carboxylic acid (C) is obtained by hydrolysis of the separated (2S, 1'R) -phenylamide derivative (B) (2S, 1'R, 2'S) trans-alcohol of the above formula (1), which is a product, can be prepared.

However, when the final product is prepared by the above-described method, the yield is as low as 32%, and impurities are generated in the same amount as the final product in the reduction reaction. In addition, when purified by column chromatography to remove the impurities, both the final product and the impurities are highly polar and are unsuitable for industrial production because it is difficult to separate the desired end product in high purity.

Yuichi Kobayashi et al. (Org. Lett., 2009 , 11, 1103-1106) discloses a process for preparing a 2S, 1'R, 2'S) trans- ] Was disclosed.

[Reaction Scheme 2]

According to this method, the cyclopentanol derivative (E) is prepared by using the derivative (D) of the cyclopentene diol as a starting material in 8 steps, reacting it with the picolinate (F) (2S, 1'R, 2'S) trans-alcohol of the above formula (1), which is an end product, can be prepared through the following processes.

However, in the above method, it is difficult to synthesize a derivative (D) of the cyclopentene diol as a starting material, and a very expensive reagent such as cis-4-cyclopentene-1,3-diol should be used in the synthesis. In addition, the ozone decomposition reaction is not suitable for industrial mass production, and has a problem of low yield and high production cost since it is subjected to a complicated manufacturing step of 15 steps.

In addition, Tomio Yamakawab et al. ( Synlett , 2000 , 6, 862-864) discloses a method for preparing a 2S, 1R, 2S trans-alcohol of the above formula (1) A manufacturing method has been disclosed.

[Reaction Scheme 3]

According to the above method, the 1-α-phenylamide derivative (G) is prepared by coupling a compound of (R) -soxirane with (S) -methylbenzylamine as a chiral resolving agent, The ketone is reduced to produce a cyclopentanolamide mixture, which is then separated into a trans-mixture using column chromatography. (1'S, 2'R) -trans-alcohol mixture is removed by acetate only using the lipase, and the (1'R, 2'S) -trans-alcohol mixture (H) is obtained. (2R, 1R ', 2'S) -epimer was removed by acetylation of the hydroxy group of the resulting (1'R, 2'S) -trans- (2S, 1'R, 2'S) -trans-alcohol of the above formula (1), which is the final product, can be prepared by the hydrolysis reaction of have.

However, thin film chromatography is used to obtain the above (2S, 1R ', 2'S) -amide derivative (I), wherein _Rf (Retention factor) of the (2R, (2S, 1R ', 2'S) - amide derivative (I), the two materials are very close to each other. Further, it is necessary to hydrolyze the secondary amide of the (2S, 1R ', 2'S) -amide derivative (I). However, by using various reaction mediators such as nitrosylsulfuric acid, Is difficult to obtain.

Although much effort has been made to produce the L-losoprofen (2S, 1'R, 2'S) trans-alcohol as represented by the active metabolite of loxoprofen, as described above, This possible method has not been developed until now.

Accordingly, the present inventors have conducted various studies in order to find a production method of a trans-alcohol of Roxoroprofen (2S, 1'R, 2'S) which is improved in yield and purity and can be mass produced as compared with the conventional method. It was completed.

The present invention

(1) A method for producing a pharmaceutical composition, which comprises mixing Roxoprofen and N-methyl-D-glucamine or N-ethyl-D-glucamine of the following formula 2 and heating the same in the presence of water or an organic solvent mixed with water (2R, 1'S) of the following formula (3a) and (2S, 1'R) -Loxofroxene of the formula (3b) Obtaining a solid phase mixture,

(2) obtaining a mixture of (2S, 1'R) -ester of (2R, 1'S) and (4Sb)

(3) The cis-mixture of the formulas (6a) and (6b) is subjected to reduction reaction by the reduction reaction of the ester mixture prepared above, and the mixture of the trans-alcohol esters of the formulas (5a) ;

(4) The trans-alcohol ester mixture of the above-mentioned formulas (5a) and (5b) obtained above was reacted with lipase and vinyl acetate and then separated by column chromatography to obtain 2S, 1 ' R, 2'S) trans-alcohol ester; and

(2S, 1R, 2S) trans-alcohol ester of the formula (5a) obtained in the above step (5) 1 ' R, 2 ' S) trans-alcohol.

(In the above formulas 4a, 4b, 5a, 5b, 6a and 6b, R is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an S-ethyl lactate group).

The organic solvent may be an alcohol, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or ethylene glycol, 1,4- - diols such as pentanediol, bisphenol A, and the like.

The organic solvent may be added in an amount of 0.1 to 1 part by weight per 1 part by weight of water.

The N-methyl-D-glucamine or N-ethyl-D-glucamine may be added in an amount of 0.1 to 1.0 equivalent based on 1 equivalent of the Rocopsoprofen of the formula (2).

The esterification reaction is carried out in the presence of a reaction medium, wherein the reaction medium is a dicyclohexylcarbodiimide And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.

The reduction reaction may be performed using a reducing agent, and the reducing agent may include at least one selected from the group consisting of sodium borohydride and sodium cyanoborohydride.

The reducing agent may be added in an amount of 1 to 3 equivalents based on 1 equivalent of a mixture of (2R, 1'S) and (2S, 1'R) -ester of the general formulas (4a) and (4b).

And then recrystallizing the compound of formula (1) in ethyl acetate and hexane.

The compound of Formula 1 may have a purity of 90% or more.

The remaining solids obtained from the solid phase mixture may be heated to 90-100 DEG C in the presence of water and stirred, cooled and then adjusted to a pH of 4 to 5.5 to recover the Loxoprofen of formula (2).

The process for producing trans-alcohol of the present invention can be carried out in a high yield and in a high purity. Particularly, the loxoprofen (2S, 1'R, 2'S) trans-alcohol represented by the formula (1) prepared by the method proposed by the present invention has a purity of 90% or more and can be usefully used in the manufacture of medicines .

Further, since the present invention can obtain a mixture containing not less than 35% of each of the intermediates (2R, 1'S) and (2S, 1'R) -Loxoprofen in the form of a solid acid, A neutralization process is not required. Particularly, by removing a considerable amount of (2R, 1'R) -Loxsoprofen in the optical resolution reaction of Step 1, the epimer (2R, 1'R, 2'S) trans - As the compound is contained in a small amount, the hydrolysis reaction can be carried out directly without separation of the chromatography in step 5 to be described later. Therefore, it is possible to mass-produce the compound of the formula (1) and reduce the production cost.

As used herein, the term " alkyl " refers to linear or branched hydrocarbons having 1 to 10 carbon atoms. Examples of alkyl include methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, hexyl, heptyl, octyl,

The term ' cycloalkyl ' refers to cyclic hydrocarbons having 3 to 6 carbon atoms. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The process for the production of the L-isoprofen (2S, 1'R, 2'S) trans-alcohol according to the invention

(1) a method of mixing Roxoprofen of the following formula (2) with N-methyl-D-glucamine or N-ethyl-D-glucamine and mixing water alone or an organic solvent which is miscible with water (2R, 1'S) and (2S, 1'R) -loxorphenes of the following formula (3b) are dissolved in 35 (Hereinafter referred to as "step 1").

(2) a step of esterifying the solid phase mixture obtained above to prepare a (2S, 1'R) -ester mixture of (2R, 1'S) and (4Sb) ")

(3) The cis-mixture of the formulas (6a) and (6b) is subjected to reduction reaction by the reduction reaction of the ester mixture prepared above, and the mixture of the trans-alcohol esters of the formulas (5a) (Hereinafter referred to as "step 3").

(4) Reaction of a mixture of trans-alcohol esters of the general formulas (5a) and (5b) with lipase and vinyl acetate followed by separation by column chromatography yields 2S, 1'R, 2'S ) To obtain a trans-alcohol ester (hereinafter referred to as "step 4").

(5) a step of hydrolyzing a (2S, 1'R, 2'S) trans-alcohol ester of loxoprofen of formula (5a) (hereinafter referred to as "step 5" (2S, 1 ' R, 2 ' S) trans-alcohol.

The process for producing the above-described rosoprofen (2S, 1'R, 2'S) trans-alcohol is a reaction process as shown in the following Reaction Scheme 4, and each step will be described in detail.

[Reaction Scheme 4]

Step 1; (2S, 1 ' R) - (2R, 1 ' S) Rocksoflopen  Obtaining the contained solid phase mixture

In step 1, as shown in Reaction Scheme 5 below, Loxoprofen and N-methyl-D-glucamine, which are starting materials of the following Chemical Formula 2, and N- D-glucamine, and heating and reacting in the presence of water or a solvent in which an organic solvent is mixed with water to dissolve and react. The precipitated crystals are then filtered to obtain the following [ (2R, 1'S) and (2S, 1'R) -Loxofroxene of formula (3a) can be obtained.

[Reaction Scheme 5]

The starting material, loxoprofen, has two chiral centers structurally, and (2R, 1'R), (2S, 1'R), (2R, Lt; RTI ID = 0.0 > of enantiomers. ≪ / RTI >

After adding N-methyl-D-glucamine or N-ethyl-D-glucamine to the Rocopsoprene, And the mixture is heated in the presence of a solvent mixed with an organic solvent to be melted and reacted. Then, when the temperature is lowered, 50 to 70% of the enantiomers having the (2S, 1'R) orientation of (2R, 1'S) precipitate in a free acid state without forming a salt with the glucamine (2R, 1'R), (2S, 1'S) and an enantiomer having an orientation of (2R, 1'S) Forms a salt with glucamine and becomes dissolved in the liquid .

At this time, the enantiomer having the (2R, 1'R), (2S, 1'S) orientation is partially precipitated in the free acid state.

Therefore, it is possible to minimize the content of the enantiomer having the orientation of (2R, 1'R), (2S, 1'S) in the free acid state, The above procedure can be repeated to increase the yield and purity of the enantiomer having the orientation.

The N-methyl-D-glucamine or N-ethyl-D-glucamine is a chiral resolving agent and is added in an amount of 0.1 to 1.0 equivalent based on 1 equivalent of Rocopsoprofen of the formula (2) And particularly preferably 0.3 to 0.7 equivalents. When the amount of N-methyl-D-glucamine or N-ethyl-D-glucamine is less than 0.1 equivalent, the optical resolution is poor and the purity is poor. When the amount is more than 1.0 equivalent, There is a problem that the unit price is increased.

The optical resolution reaction with N-methyl-D-glucamine or N-ethyl-D-glucamine is carried out by heating to dissolve in the presence of a solvent.

The solvent may be used alone or in combination with an organic solvent which is miscible with water.

The N-methyl-D-glucamine or N-ethyl-D-glucamine can be completely dissolved in a small amount of water, and the addition of an organic solvent that is miscible with water improves the purity and yield of the solid phase mixture Can be obtained.

The organic solvent may include at least one selected from the group consisting of alcohol, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran and diols.

Examples of the diol include ethylene glycol, 1,4-butanediol, 1,3-propanediol, 1,5-pentanediol, bisphenol A, and the like.

The organic solvent is preferably added in an amount of 0.1 to 1 part by weight, more preferably 0.2 to 0.5 part by weight, per 1 part by weight of water, and a yield of less than 1 part by weight is problematic.

Further, it is preferable to raise the temperature to about 40 to 70 DEG C in order to cause the optical resolution reaction to take place well.

The molten reaction solution may be cooled to a temperature of 30 to 50 캜 and stirred for 1 hour or more, preferably 4 hours or more, to precipitate crystals. The precipitated crystals are filtered and washed with purified water, hexane, alcohol or the like and then dried to obtain an enantiomer pair containing (2R, 1'S) and (2S, 1'R) A mixture can be obtained.

The solid-phase mixture containing (2R, 1'S) and (2S, 1'R) -loxorphedron prepared by the above process is obtained as a mixture of solid phases containing not less than 35% have. Therefore, since no separate neutralization step is required, the reaction time can be greatly shortened.

(2R, 1'R, 2'S) trans (epimer) which is difficult to remove after the subsequent step by removing a considerable amount of the enantiomer having the orientation of (2R, 1'R) As the alcohol ester compound is contained in a small amount, the hydrolysis reaction can be carried out directly in Step 5, which will be described later, without separation of the chromatography.

On the other hand, the above-mentioned solid phase mixture can be recovered and the remaining filtrate can be recovered by adjusting the pH to 4 to 5.5 by raising the temperature to 90 to 100 DEG C in the presence of water and stirring and cooling.

That is, water is added to the filtrate, the temperature is raised to 90 to 100 ° C, the mixture is stirred, cooled to room temperature, and the precipitated crystals are filtered and dried to obtain a rock soap pen.

At this time, it is preferable to add hydrochloric acid to the reaction solution to maintain the pH of the reaction solution at 4 to 5.5.

Further, in order to increase the recovery rate of the above-mentioned rosoprofen, the recovery process may be performed several times. Through the process of recovering the filtrate, it is possible to reduce the manufacturing cost and improve the economical efficiency by obtaining the liquid soap.

Step 2. Preparation of (2S, 1'R) -ester mixture of (2R, 1'S) and [4b]

In Step 2, as shown in Reaction Scheme 6 below, the solid phase mixture obtained in Step 1 is subjected to esterification reaction to obtain (2S, 1'S) and (2S, 1 ' R) -ester mixture can be prepared.

[Reaction Scheme 6]

The esterification reaction can be carried out in the presence of a reaction medium. The reaction medium can convert the hydroxy group of the carboxylic acid to the ester group by esterifying the solid phase mixture. That is, the reaction medium removes H from the hydroxyl group to form an urea-type intermediate, and then reacts with an alcohol to obtain (2S, 1S) and (2S , 1 ' R) -ester mixture can be prepared.

The reaction medium may be selected from the group consisting of dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) And may include at least one selected.

Further, the esterification reaction can be carried out using an alcohol, a cycloalcohol or a chiral alcohol of S-ethyllactate, preferably methanol or S-ethyllactate good. The above-mentioned methanol or S-ethyl lactate (S-ethyllactate) can easily carry out the reaction even at a low temperature since the ester group of the formula (5a) can be easily deprotected during the hydrolysis reaction of 5 steps described later.

(2S, 1'S) of the formula (4a) and (2S, 1'R) of the formula (4b) can be obtained by reacting the alcohol, the cycloalcohol or the chiral alcohol of S- ethyllactate, ) -Ester mixture is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, or an S-ethyllactate group as a chiral alcohol.

The esterification reaction can be carried out by dissolving the obtained solid phase mixture in a solvent such as dichloromethane, and sequentially adding a reaction medium and an alcohol thereto.

(2S, 1'R) of formula (4b) and (2S, 1'R) of formula (4b) can be obtained by stirring, extracting and concentrating under reduced pressure at room temperature the solvent, reaction medium and alcohol to the solid mixture, -Ester mixture can be obtained.

For example, the reaction solution is stirred at room temperature for at least 30 minutes, preferably at least 1 hour, extracted with water, and then washed with sodium chloride solution. Then, the organic layer of the washed reaction solution was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain (2R, 1'S) ester of the formula (4a) R) -ester mixture can be prepared.

Step 3. Obtaining a mixture of trans-alcohol esters of formulas (5a) and (5b)

In step 3, a mixture of (2S, 1'R) -ester mixture of (2R, 1'S) and [4b] of the formula 4a prepared in the step 2 as shown in the following scheme 7 and scheme 8 And then the cis-mixture of the formulas (6a) and (6b) is removed by column chromatography to obtain a trans-alcohol ester mixture of the formulas (5a) and (5b).

[Reaction Scheme 7]

[Reaction Scheme 8]

The reduction reaction may be carried out using a reducing agent. The reducing agent may be converted to the cyclopentanol by reducing the cyclopentanone ketone group in the compounds of formulas (4a) and (4b) with an alcohol by reducing the ester mixture.

It is preferable that the reducing reaction is performed by using a hydride-based reducing agent in order to reduce only the ketone group without reacting with the carboxyl groups in the compounds of the formulas (4a) and (4b). Specifically, the reducing agent may include at least one selected from the group consisting of sodium borohydride or sodium cyanoborohydride.

The reducing agent is preferably added in an amount of 1 to 3 equivalents, more preferably 1 to 2 equivalents based on 1 equivalent of the (2S, 1'R) -ester mixture of (2R, 1'S) and [4b] desirable. When the reducing agent is used in the above range, the reduction reaction sufficiently occurs, and the ketone groups of the compounds of the formulas (4a) and (4b) can be efficiently reduced.

In addition, the reduction reaction is accompanied by a cis-alcohol ester mixture of the general formulas (6a) and (6b) in addition to the desired trans-alcohol ester mixture of the general formulas (5a) and (5b).

Thus, chromatography may be used to remove the cis-alcohol ester mixture and to separate the trans-alcohol ester mixture. The chromatography preferably uses column chromatography, which can easily separate a mixture of liquid phases.

The reduction reaction with a (2S, 1'R) -ester mixture of (2R, 1'S) and (4b) in the above formula (4a) can be carried out by dissolving in a solvent such as methanol or tetrahydrofuran and adding a reducing agent have.

Further, the reduction reaction may be carried out under stirring, under reduced pressure and concentration under cooling conditions.

For example, a reaction solution obtained by adding a solvent to a (2S, 1'R) -ester mixture of (2R, 1'S) and (2S, 1'R) -ester of the formula 4a is cooled to 0 ° C and the reducing agent is gradually added Then, the reaction is carried out by stirring for 30 minutes or more, preferably 1 hour or more.

At this time, the reaction may be carried out at room temperature for 10 hours or more, preferably 16 hours or more, in order to proceed the reaction completely.

Then, when the reaction is completed, the reaction solution is concentrated under reduced pressure. The residue on an oil phase is subjected to solvent fractionation using dichloromethane or hexane, and then washed with water or sodium chloride. The organic layer of the washed reaction solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture of trans-alcohol ester mixture and cis-alcohol ester, which was separated by column chromatography to obtain A trans-alcohol ester mixture can be obtained.

Step 4. Preparation of Loxophrofen (2S, 1'R, 2'S) trans-alcohol ester

In step 4, a trans-alcohol ester mixture of the formulas (5a) and (5b) separated in the step 3 is reacted with lipase and vinyl acetate as shown in the following reaction scheme 9 (2S, 1'R, 2'S) trans-alcohol ester of formula (5a) can be obtained by column chromatography.

[Reaction Scheme 9]

As shown in Reaction Scheme 9 above, when a lipase and vinyl acetate are added to a trans-alcohol ester mixture of formulas (5a) and (5b) and reacted, only the compound of formula (5b) is selectively subjected to an acetylation reaction To give a compound of formula (7). That is, when a mixture of trans-alcohol esters of the general formulas [5a] and [5b] is reacted with lipase and vinyl acetate, only the hydroxy group of the compound of the general formula [5b] is stereoselectively acetylated. On the other hand, since the compound of the formula (5a) is not acetylated, the acetylated compound of the formula (7) and the compound of the formula (5a) can be separated by column chromatography.

The acetylation reaction catalyzed by the lipase can be carried out using a known method ( Synlett , 2000 , 6, 862-864).

The lipase may be Amano Lipase PS or the like. The lipase is preferably added in an amount of 5 to 15% by weight, more preferably 8 to 12% by weight, based on 100% by weight of the trans-alcohol ester mixture of the formulas (5a) and (5b) . When the lipase is used in the above range, sufficient selective acetylation of the compound of Formula 5b can be achieved.

Chromatography can also be used to separate the acetylated compounds of formula (7) and (5a). The chromatography preferably uses column chromatography, which can easily separate a mixture of liquid phases.

The acetylation reaction of the trans-alcohol ester mixture of the above formulas (5a) and (5b) can be carried out by dissolving the compound in toluene as a solvent and adding lipase and vinyl acetate. In addition, the acetylation reaction can be carried out at room temperature under stirring, under reduced pressure, and purification.

For example, a solvent is added to and dissolved in a mixture of trans-alcohol esters of the general formulas [5a] and [5b], followed by sequentially adding lipase, molecular sieve and vinyl acetate, Is reacted by stirring for 20 hours or more. Then, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain a crude product of the oil phase (2S, 1'R, 2'S) trans-alcohol Ester can be obtained.

Step 5. Synthesis of Loxophrofen  Preparation of (2S, 1'R, 2'S) trans-alcohol

In step 5, hydrolysis of the (2S, 1'R, 2'S) trans-alcohol ester of loxoprofen (formula 5a) isolated in step 4 as shown in the following scheme [Reaction formula 10] (2S, 1'R, 2'S) trans-alcohol of the formula (I) can be prepared.

[Reaction Scheme 10]

The above-mentioned trans-alcohol ester compound of the formula (5a) can be converted into a hydroxy group by reacting the ester group of the carboxylic acid in the compound of the formula (5a) with a hydrolysis reaction.

The hydrolysis of the (2S, 1'R, 2'S) trans-alcohol ester compound of the formula (5a) is preferably carried out in the presence of an acid or base to increase the reaction rate.

The acid may be an organic acid such as hydrochloric acid, sulfuric acid, or hydrogen bromide, or an inorganic acid such as formic acid, acetic acid, or p-toluenesulfonic acid. The base may be lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like.

In addition, the hydrolysis reaction may be performed by dissolving in a solvent such as acetonitrile, and conducting stirring, extraction, and concentration under reduced pressure under cooling conditions.

For example, a reaction solution obtained by adding a solvent to a trans-alcohol ester compound of the formula (5a) is gradually cooled to 0 to 5 占 폚 and then slowly added with water and an acid or a base. Or more. Then, ethyl acetate and water are added to extract, and then the aqueous layer is separated.

At this time, in order to adjust the pH to 3 to 3.5, it is preferable to add hydrochloric acid to the separated aqueous layer and then perform extraction twice or more with dichloromethane.

Therefore, the extracted reaction solution is dried with anhydrous sodium sulfate and filtered, and then the filtrate is concentrated under reduced pressure to prepare a loxoprofen (2S, 1'R, 2'S) trans-alcohol of formula (1).

Further, the compound of formula (I) prepared above may be further purified by further recrystallizing in an organic solvent in order to increase the purity.

The recrystallization may be carried out using an organic solvent of ethyl acetate and hexane.

To the prepared through the above steps, a compound of Formula 1 is a soft rock with a pen (2S, 1'R, 2'S) trans-alcohol as a, and its chemical name is (2 S) -2- [4 - ((1 R , 2S ) -2-hydroxycyclopentylmethyl) phenyl] propionic acid.

[Chemical Formula 1]

According to the present invention, the (2S, 1'R, 2'S) trans-alcohol of Roxsoprofen of the formula (1) can be produced with a purity of 90% or more.

Further, when the above-prepared rocks isopropyl (2S, 1'R, 2'S) trans-alcohol is further recrystallized, its purity can be increased to 95% or more.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope and spirit of the invention as disclosed in the accompanying drawings. And it is obvious that such variations and modifications are included in the appended claims.

[ Used equipment  And measurement conditions]

In the following examples, the purity of the compounds was determined by chiral high performance liquid chromatography (CHIRAL HPLC). (CHIRALCEL, AD-H column, 250 X 4.6 mm) and mobile phase (n-hexane: ethanol: trifluoroacetic acid: diethylamine = 900: 100: 1: 1) , An oven temperature of 40 ^° C and a wavelength of 220 nm.

< Example  1> Step 1. Preparation of (2S, 1'R) - (2R, 1'S) Rocksoflopen  Obtain a solid mixture containing

Method A

500 g of Loxoprofen and 200 g of N-methyl-D-glucamine were placed in a container. A mixed solvent of 2500 ml of water and 500 ml of ethanol was added, and the temperature was raised to about 60 캜 to dissolve completely. The dissolved reaction solution was slowly cooled to about 45 캜 and stirred at about 45 캜 for 4 hours to precipitate crystals. The precipitated crystals were then slowly cooled to about 35 ° C and stirred for 1 hour. The crystals were filtered, washed with 500 ml of water and dried under a warm air at about 40 ° C to obtain (2R, 1'S) and (2S, 1'R) 165 g (yield 33%) of a solid-phase mixture containing pen was obtained.

Purity (2S, 1'R-isomer 44.5%, 2R, 1'S-isomer 44.5%, 2R, 1'R-isomer 5.5%, 2S,

Method B

160 g of the solid phase mixture containing the [Formula 3a] and [Formula 3b] prepared in Method A and 25 g of N-methyl-D-glucamine were introduced into a vessel, and a mixed solvent of 480 ml of water and 240 ml of ethanol was added After the temperature was raised to about 60 ° C, it was completely dissolved. The dissolved reaction solution was added with 160 ml of water at about 60 캜, slowly cooled to about 45 캜, and stirred for 4 hours to precipitate crystals. Then, the precipitated crystals were slowly added with water (640 ml) at about 45 ° C for 30 minutes, and then stirred for 1 hour to precipitate crystals once more. The precipitated crystals were filtered, washed with 400 ml of water and dried in a warm air at about 40 ° C to obtain (2R, 1'S) and (2S, 1'R) 125 g (yield 78%) of a solid phase mixture containing loxoprofen was obtained.

Purity (2S, 1'R-isomer 48.5%, 2R, 1'S-isomer 48.7%, 2R, 1'R-isomer 1.4%, 2S,

Method C

(2R, 1'S) and (2S, 1'R) -Loxoprofen of the formula [3aa] were obtained by using acetone instead of ethanol in the same manner as in the method A, 132 g (yield: 26%) of the mixture was obtained.

Purity (44.1% of 2S, 1'R-isomer, 44.1% of 2R, 1'S-isomer, 5.9% of 2R, 1'R- isomer, 2.9% of 2S,

Method D

(2S, 1'R) -Loxoprofen of formula (3a) and (2R, 1'S) of formula (3b) were obtained by using acetonitrile instead of ethanol, 120 g (yield: 24%) of a solid phase mixture was obtained.

Purity (2S, 1'R-isomer 45.7%, 2R, 1'S-isomer 45.4%, 2R, 1'R-isomer 4.2%, 2S, 1'S- isomer 4.7%

Method E

(2S, 1'R) -Loxofluoro (2R, 1'S) of the formula [3a] and the compound of the formula [3b] were obtained in the same manner as in the method A, except that N, N-dimethylformamide was used instead of ethanol. 164 g (yield: 33%) of a solid-phase mixture containing pen was obtained.

Purity (2S, 1'R-isomer 43.0%, 2R, 1'S-isomer 43.0%, 2R, 1'R-isomer 7.0%, 2S,

Method F

(2S, 1'R) -Loxoprofen (2S, 1'R) of the formula (3a) and the compound of the formula (3b) were obtained by using water alone instead of the mixed solvent of water and ethanol. (Yield: 23%) was obtained.

Purity (2S, 1'R-isomer 43.3%, 2R, 1'S-isomer 43.4%, 2R, 1'R-isomer 6.6%, 2S, 1'S- isomer 6.6%

In Step 1, according to Method F using water as a solvent, the yield of the solid phase mixture containing [Formula 3a] and [Formula 3b] is about 23%, but in the form of a mixed solvent containing an organic solvent in addition to water as a solvent It can be seen that the methods A to E used have a slightly improved yield as compared with the method F. [

Further, it is understood that the purity of the solid phase mixture containing [Formula 3a] and [Formula 3b] obtained in Methods A, C, D, E and F is increased when the process of Method B is further repeated .

< Example  2> Step 2. Preparation of (2S, 1'R) -ester mixture (R: methyl group) of (2R, 1'S)

100 g of a solid mixture containing the [Formula 3a] and [Formula 3b] prepared in Method B of Example 1 above was added to the vessel and dissolved in 1000 ml of dichloromethane. After adding 116.7 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 5.0 g of N, N-dimethylaminopyridine to the reaction solution, 25 ml of methanol was slowly added. Then, the mixture was stirred at room temperature for 1 hour, extracted with 1000 ml of water, and then washed with 1000 ml of 20% aqueous sodium chloride solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain (2R, 1'S) and (2S, 1'R) - ester mixture (yield: 100%).

< Example  3> Step 3. Obtaining a mixture of trans-alcohol esters of the general formulas (5a) and (5b) (R: methyl group)

105.7 g of a (2S, 1'R) -ester mixture of (2R, 1'S) and [4b] of the formula 4a prepared in Example 2 was dissolved in 1000 ml of methanol, Lt; / RTI &gt; Maintaining the temperature, and a hydride (NaBH ₄₎ 18.4g of sodium beam was slowly added. Then, the reaction solution was stirred at 0 ° C for 1 hour, concentrated under reduced pressure, and then subjected to solvent fractionation with 1000 ml of dichloromethane in an oil phase residue. The separated organic layer was washed twice with 1000 ml of water, and then once again with 1000 ml of 20% aqueous sodium chloride solution. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a mixture of cis-alcohol esters of the residue (trans-alcohol ester mixture of formulas 5a and 5b: cis-alcohol esters of formula 6a and formula 6b = 79.2 : 20.8) was separated by column chromatography (ethyl acetate: n-hexane = 1: 10). The mixture of cis-alcohol esters of the above formulas (6a) and (6b) was removed to obtain 50.5 g (yield: 48%) of a mixture of trans-alcohol esters of the formula (5a) and (5b)

< Example  4> Step 4. Synthesis of [Formula 5a] Loxophrofen (2S, 1'R, 2'S) trans-alcohol ester (R: methyl group)

30.5 g of the trans-alcohol ester mixture of the formulas (5a) and (5b) prepared in Example 3 was added to the container and dissolved in 92 ml of toluene. Then 3.4 g of Amano Lipase PS, 3.4 g of molecular sieves 3 Å powder and 32.1 ml of vinyl acetate were added to the reaction solution, followed by stirring at room temperature for 20 hours. The reaction solution was filtered, and the remaining filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 6) 13.6 g (yield: 45%) of pen (2S, 1'R, 2'S) trans-alcohol ester was obtained.

< Example  5> Step 5. A compound of formula Loxophrofen  (2S, 1'R, 2'S) trans-alcohol production

13.6 g of the trans-alcohol ester compound of the formula 5a prepared in Example 4 was added to the vessel and dissolved in 135 ml of acetonitrile. Then, the solution was cooled to about 0 ° C, and an aqueous solution in which 6.5 g of lithium hydroxide monohydrate (LiOH.H ₂ O) was dissolved in 135 ml of water was gradually added to the solution while maintaining the temperature at about 0 ° C, Lt; / RTI &gt; Then, 270 ml of ethyl acetate was added, and the mixture was extracted with 270 ml of water, and the aqueous layer was separated. The separated aqueous layer was adjusted to about pH 3 with 6N hydrochloric acid, extracted twice with 135 ml of dichloromethane, and dried over anhydrous magnesium sulfate. Then, the dried reaction solution was filtered and concentrated under reduced pressure, and then 41 ml of ethyl acetate was added to dissolve it. Subsequently, 272 ml of n-hexane was slowly added, stirred at room temperature for 1 hour, and then filtered. The filtrate was vacuum-dried at 25 占 폚 to obtain 11.0 g (yield: 88%) of rosoprofen (2S, 1'R, 2'S) trans-alcohol as a target compound in the form of a solid.

Purity (2S, 1'R, 2'S-isomer 94.5%, 2R, 1'R, 2'S-isomer (epimer) 5.5%

_{^{1 H-NMR (CDCl 3)}} δ: 1.12 ~ 1.29 (m, 1H), 1.41 ~ 1.77 (m, 3H), 1.48 (d, 3H), 1.77 ~ 1.89 (m, 1H), 1.90 ~ 2.07 (m, 2H), 2.44 (dd, 1H), 2.73 (dd, 1H), 3.68 (q, d, 2H)

< Example  6> Step 1. Preparation of (2S, 1'R) - (2R, 1'S) Rocksoflopen  Obtain a solid mixture containing

Same as Method B of Example 1 above

< Example  Step 2: Preparation of (2S, 1'R) -ester mixture of (2R, 1S) and (4S) Ethyl lactate group )

100 g of a solid phase mixture containing the [Formula 3a] and [Formula 3b] prepared in Method B of Example 6 above was added to the vessel and dissolved in 1000 ml of dichloromethane. After 116.7 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 5.0 g of N, N-dimethylaminopyridine were added to the reaction solution, 69.5 ml of (S) -ethyl lactate was gradually added. Then, the mixture was stirred at room temperature for 1 hour, extracted with 1000 ml of water, and then washed with 1000 ml of 20% aqueous sodium chloride solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain (2R, 1'S) and (2S, 1'R) -Ester mixture (yield: 100%).

< Example  8> Step 3. Obtaining a mixture of trans-alcohol esters of formulas (5a) and (5b) (R: (S) - Tilaclate group )

140.6 g of a (2S, 1'R) -ester mixture of (2R, 1'S) and (4Sb) [Formula 4a] prepared in Example 7 was added to a vessel and dissolved in 1,400 ml of tetrahydrofuran 232 ml of acetic acid was added. Then, the reaction solution was cooled to 0 캜, and 38.3 g of sodium cyanoborohydride (NaCNBH ₃ ) was slowly added thereto while maintaining the above temperature. Then, the reaction solution was stirred at 0 ° C for 1 hour, and after refluxing at room temperature for 16 hours, 815 ml of water was added. Then, the reaction solution was extracted with 1055 ml of ethyl acetate and re-extracted with 280 ml of ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue (trans-alcohol ester mixture of the formula 5a and the compound of the formula 5b: cis-alcohol ester mixture of the formula 6a and the formula 6b) 77:23) was separated by column chromatography (ethyl acetate: n-hexane = 1: 10). The mixture of cis-alcohol esters of the above formulas (6a) and (6b) was removed to obtain 65 g (yield: 46%) of a mixture of the trans-alcohol esters of the formula (5a) and the formula (5b)

< Example  9> Step 4. A compound of the formula 5a Loxophrofen (2S, 1'R, 2'S) trans-alcohol ester (R: (S) - Ethyl lactate group )

To the vessel was added 65 g of the trans-alcohol ester mixture of the formulas (5a) and (5b) prepared in Example 8, and dissolved in 195 ml of toluene. Then, 7.2 g of Amano Lipase PS, 7.2 g of molecular sieves 3 Å powder and 51.6 ml of vinyl acetate were added to the reaction solution, followed by stirring at room temperature for 20 hours. The reaction solution was filtered, and the remaining filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 6) (2S, 1'R, 2'S) trans-alcohol ester (yield: 47%).

< Example  10> Step 5. Preparation of the compound of formula Loxophrofen  (2S, 1'R, 2'S) trans-alcohol production

29.3 g of the trans-alcohol ester compound of the formula (5a) prepared in Example 9 was added to the container and dissolved in 293 ml of acetonitrile. Then, the solution was cooled to about 0 캜, and an aqueous solution obtained by dissolving 39.1 g of lithium hydroxide monohydrate (LiOH.H ₂ O) in 293 ml of water was slowly added to the solution while keeping the temperature at about 0 캜, Lt; / RTI &gt; Then, 590 ml of ethyl acetate was added, and the mixture was extracted with 590 ml of water to separate the aqueous layer. The separated aqueous layer was adjusted to about pH 3 with 6N hydrochloric acid, extracted twice with 290 ml of dichloromethane, and dried over anhydrous magnesium sulfate. The dried reaction solution was filtered, concentrated under reduced pressure, and dissolved in 88 ml of ethyl acetate. Subsequently, 586 ml of n-hexane was slowly added, stirred at room temperature for 1 hour, and then filtered. The filtrate was vacuum-dried at 25 占 폚 to obtain 17.9 g (yield: 85%) of a solid (2S, 1'R, 2'S) trans-alcohol of the formula (1).

Purity (2S, 1'R, 2'S-isomer 94.3%, 2R, 1'R, 2'S-isomer (epimer) 5.7%

_{^{1 H-NMR (CDCl 3)}} δ: 1.12 ~ 1.29 (m, 1H), 1.41 ~ 1.77 (m, 3H), 1.48 (d, 3H), 1.77 ~ 1.89 (m, 1H), 1.90 ~ 2.07 (m, 2H), 2.44 (dd, 1H), 2.73 (dd, 1H), 3.68 (q, d, 2H)

The unreacted loxoprofen according to the present invention can be recovered in the following manner.

One) Loxophone  Recovery method ①

To the vessel was prepared the solid mixture in the methods A and B of Example 1 and the remaining filtrate and 360 ml of water were added. Then, the pH was adjusted to 5.5 with 2N-HCl at room temperature, and when the pH rose as the crystals were precipitated, the pH was adjusted to 5.5 with 2N HCl for about 30 minutes. When the crystals were sufficiently precipitated, the pH was adjusted to 5.0 with 2N-HCl. When the pH was increased, the pH was further adjusted to 5.0 over about 30 minutes. Then, the solution was slowly adjusted to pH 4.0 with 2N-HCl, stirred for 1 hour, and the precipitated crystals were filtered. The precipitated crystals were washed with 200 ml of water and dried in a warm air at about 40 ° C to recover 34 g of raloxifene.

Purity (2S, 1'R-isomer 19.8%, 2R, 1'S-isomer 19.8%, 2R, 1'R- isomer 30.2%, 2S, 1'S- isomer 30.2%

2) Loxophone  Recovery method ②

20 g of Rocopsoprene recovered in Reference Example 1) and 100 ml of water were added to the container. Then, the reaction solution was heated to about 95 캜, stirred for 15 hours, cooled to room temperature, and then 200 ml of water was added. The mixture was then adjusted to pH 4.0 slowly using 2N-HCl, and crystals were precipitated. The precipitated crystals were filtered, washed with 100 ml of water, and dried in a warm air stream to recover 18.8 g (94% yield) of Rocsoprofen.

Purity (2S, 1'R-isomer 25.1%, 2R, 1'S-isomer 25.1%, 2R, 1'R-isomer 24.7%, 2S, 1'S- isomer 24.7%

(2S, 1'R, 2'S) trans-alcohol of the formula 1 of Example 5, which was prepared through Examples 1-5 of the present invention, and Example 6 (2S, 1'R, 2'S) trans-alcohol of the formula [1] of Example 10, which was prepared through the above steps 10 to 10, had a yield of 85% or more and a purity of 90% or more in the final stage have. On the other hand, according to the conventional U.S. Patent No. 4,400,534, the final yield of the lithosuprophen (2S, 1'R, 2'S) trans-alcohol of the formula 1 finally prepared is as low as 32% (2S, 1'R, 2'S) trans-alcohol of formula (1) produced in large quantities was finally reduced.

Claims (10)

(1) A method for producing a pharmaceutical composition, which comprises mixing Roxoprofen and N-methyl-D-glucamine or N-ethyl-D-glucamine of the following formula 2 and heating the same in the presence of water or an organic solvent mixed with water (2R, 1'S) of the following formula (3a) and (2S, 1'R) -Loxofroxene of the formula (3b) Obtaining a solid phase mixture,
(2) producing a mixture of (2S, 1'R) -ester of (2R, 1'S) and (4b) of the following formula (4a) by esterification reaction of the racemic mixture obtained above,
(3) The cis-mixture of the formulas (6a) and (6b) is subjected to reduction reaction by the reduction reaction of the ester mixture prepared above, and the mixture of the trans-alcohol esters of the formulas (5a) ;
(4) A mixture of the trans-alcohol esters of the formulas (5a) and (5b) obtained above was reacted with lipase and vinyl acetate, and then separated by column chromatography to obtain 2S, 1 ' R, 2'S) trans-alcohol ester; and
(5) hydrolyzing a (2S, 1'R, 2'S) trans-alcohol ester of the above-obtained Loxoprenoprene of the formula (5a)
Wherein the organic solvent of step (1) comprises at least one selected from the group consisting of alcohols, acetone, acetonitrile and N, N-dimethylformamide. 1 ' R, 2 ' S) trans-alcohol:
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(In the above formulas 4a, 4b, 5a, 5b, 6a and 6b, R is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an S-ethyl lactate group).
delete The method according to claim 1,
(2S, 1'R, 2'S) trans-alcohol is added in an amount of 0.1 to 1 part by weight per 1 part by weight of water.
The method according to claim 1,
Wherein the N-methyl-D-glucamine or N-ethyl-D-glucamine is added in an amount of 0.1 to 1.0 equivalent based on 1 equivalent of the Rocopsoprofen of the formula (2) 2S, 1'R, 2'S) trans-alcohol.
The method according to claim 1,
Wherein the esterification reaction is carried out in the presence of a reaction medium, wherein the reaction medium comprises at least one selected from the group consisting of dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2S, 1'R, 2'S) trans-alcohol.
The method according to claim 1,
Wherein the reduction reaction is carried out using a reducing agent, and the reducing agent comprises at least one selected from the group consisting of sodium borohydride and sodium cyanoborohydride. , 2'S) trans-alcohol.
The method of claim 6,
The reducing agent is added in an amount of 1 to 3 equivalents based on 1 equivalent of a (2S, 1'R) -ester mixture of (2R, 1'S) and (2S, 1'R) -ester of the formula (4a) 2S, 1'R, 2'S) trans-alcohol.
The method according to claim 1,
(2S, 1'R, 2'S) trans-alcohol, characterized in that it further comprises a step of recrystallization after the step of producing the compound of the formula (1).
The method according to any one of claims 1 and 3 to 8,
(2S, 1'R, 2'S) trans-alcohol characterized in that the compound of the formula (1) has a purity of 90% or more.
The method of claim 9,
The solid phase mixture is obtained, and the remaining filtrate is heated to 90 to 100 DEG C in the presence of water, stirred and cooled, and then adjusted to pH 4 to 5.5 to recover the Loxofropene of formula (2) (2S, 1'R, 2'S) trans-alcohol.