KR101465025B1 - The stereoselective manufacturing method of loxoprofen(2s, 1'r, 2'r) trans-alcohol - Google Patents

Abstract

[화학식 2]

[화학식 3]

[화학식 4]

[화학식 5]

[화학식 6]

(상기 화학식 3에서, X는 Cl 또는 Br이고, 화학식 4a, 4b, 5a, 5b, 6a 및 6b에서, R은 S-에틸락테이트기(S-ethyl lactate)이다.).
(2S, 1'R, 2'S) trans-alcohol capable of improving yield and purity, and more particularly, to a process for preparing a stereoselective Rocsoprofen Reacting the pen with a halogenating agent to obtain an acyl halide mixture of the following formula 3 and concentrating, reacting the concentrate with a tertiary amine, cooling to -78 to -70 ° C and reacting with S-ethyl lactate, Ethyl lactate ester mixture containing at least 40% of each of [Formula 4a] and [Formula 4b] is prepared by reducing the S-ethyl lactate ester mixture prepared above, To obtain a trans-alcohol ester mixture of formula (5b), the trans-alcohol ester mixture obtained above is reacted with lipase and vinyl acetate and then separated by column chromatography (2S, 1'R, 2'S) trans-alcohol ester of the formula (5a), and a step of obtaining a lysoprofen - hydrolyzing the alcohol ester.
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

X is Cl or Br, and R is S-ethyl lactate in the formulas 4a, 4b, 5a, 5b, 6a and 6b.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing stereoselective oxytocin (2S, 1'R, 2'S) trans-

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

[Chemical Formula 1]

In general, Loxoprofen, 2- [4- (2-oxocyclopentylmethyl) 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, cyclopentanone ketone is directly reduced to alcohol by the reduction reaction of the enzyme in the body to produce cyclopentanol 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 trans having an orientation of (2S, 1'R, 2'S) 2S, 1'R, 2'S) trans-alcohol has been reported 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 the final product, can be prepared by separation by column chromatography.

However, when the final product is prepared by the above-described method, the yield is as low as 32%, and impurities are produced in almost the same amount as the final product during 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 the above method, the cyclopentanol derivative (E) is prepared by using the derivative (D) of the cyclopentenediol as a starting material in five steps, reacted 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 above process.

However, in the above method, it is difficult to synthesize a derivative (D) of a cyclopentenediol 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 in low yield and high production stage 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 is disclosed.

[Reaction Scheme 3]

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

However, thin film chromatography is used to obtain the (2S, 1'R, 2'S) -amide derivative (I), wherein the R _f (retention factor) position of the (2R, Is very close to the (2S, 1'R, 2'S) - amide derivative (I), and the fraction of the two substances is large. Further, it is necessary to hydrolyze the secondary amide of the (2S, 1'R, 2'S) -amide derivative (I). However, by using various reaction mediators such as nitrosylsulfuric acid, It is difficult to obtain the product.

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.

The inventors of the present invention have conducted various studies to find a method for producing a rocksoprofen (2S, 1'R, 2'S) trans-alcohol having a higher yield and purity than the conventional method and stereoselectively. It was completed.

The present invention

(1) reacting Roxsoprofen of the following formula (2) with a halogenating agent to obtain an acyl halide mixture of the following formula (3), concentrating the resulting mixture, dissolving the concentrate in a solvent, (2S, 1S) - compound of the following formula (4a) and (2S, 1S) - compound of the formula (4b) by reacting with a tertiary amine, 1 ' R) -compound, each containing at least 40% of the S-ethyl lactate ester mixture,

(2) The S-ethyl lactate ester mixture prepared above is subjected to a reduction reaction, and then the cis-mixture of the following formulas (6a) and (6b) is removed by column chromatography to obtain the following formula (5a) Of a trans-alcohol ester mixture,

(3) A mixture of trans-alcohol esters of the above 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

(4) hydrolyzing the (2S, 1'R, 2'S) trans-alcohol ester of the loxoprofen of formula (5a) obtained above to form a stereoselective L- (2S, 1 ' R, 2 ' S) trans-alcohol.

Wherein X is Cl or Br, and R is S-ethyl lactate in the general formulas 4a, 4b, 5a, 5b, 6a and 6b.

The halogenating agent consisting of thionyl chloride (SOCl _2), phosphorus trichloride (PCl _3), phosphorus pentachloride (PCl _5), save phosphorus tribromide (PBr _3), five bromide in (PBr ₅₎ and yeomhwaok (COCl) ₂ At least one selected from the group consisting of < RTI ID = 0.0 >

The halogenating agent may be added in an amount of 1 to 2 equivalents based on 1 equivalent of Rocopsoprofen of the formula (2).

The solvent may include at least one selected from the group consisting of toluene, hexane, heptane, and tetrahydrofuran.

The tertiary amine is preferably selected from the group consisting of N -methylpyrrolidine, trimethylamine, dimethylethylamine, diisopropylethylamine, pyridine, picoline, N, N -dimethylaniline, 1,4-diazabicyclo [2.2.2] , Quinuclidine, and quinoline.

The tertiary amine may be added in an amount of 1 to 4 equivalents based on 1 equivalent of Rocopsoprofen of the formula (2).

The cooling may be carried out at a temperature of from -78 to -70 占 폚, preferably at a temperature of from -78 to -75 占 폚.

The S-ethyl lactate may be added in an amount of 1 to 1.5 equivalents based on 1 equivalent of Rocopsoprofen of the formula (2).

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 the S-ethyl lactate ester mixture.

And then recrystallizing the compound of formula (1).

The compound of the formula (1) may have a purity of 90% or more.

The process for preparing trans-alcohol (2S, 1'R, 2'S) trans-alcohol according to the present invention can produce a compound of formula (1) in a stereoselective manner at a high yield. In particular, the loxoprofen (2S, 1'R, 2'S) trans-alcohol of the formula (1) prepared by the process of the present invention has a purity of 90% or more and can be usefully used in the manufacture of medicines.

(2S, 1'S) - compound of formula (4a) and (2S, 1'S) - compound of formula (4b), which are intermediates from loxoprofen of formula (2), without using a chiral resolving agent, 1 ' R) -compounds can each be obtained at a content of at least 40%. Particularly, by removing a considerable amount of a compound having an orientation of (2R, 1'R) - in the esterification reaction of Step 1, (2R, 1'R, 2'S) trans, which is an epimer, As a small amount of the compound is contained, the hydrolysis reaction can be carried out directly in the step 4, which will be described later, without separation of the chromatography. Therefore, according to the production method of the present invention, it is possible to mass-produce the (2S, 1'R, 2'S) trans-alcohol of the Rocopsoprene of the formula (1) and reduce the production cost.

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

(1) reacting the loxoprofen of the following formula (2) with a halogenating agent to obtain an acyl halide mixture of the following formula (3) and concentrating, then dissolving the concentrate in a solvent, and carrying out in-situ (2S, 1'S) - compound of the following formula [4a] and (2S, 1'R ) - preparing a mixture of S-ethyl lactate esters each containing at least 40% of the compound, (hereinafter referred to as step 1)

(2) The S-ethyl lactate ester mixture prepared above is subjected to a reduction reaction, and then the cis-mixture of the following formulas (6a) and (6b) is removed by column chromatography to obtain the following formula (5a) To obtain a trans-alcohol ester mixture (hereinafter referred to as step 2).

(3) A mixture of trans-alcohol esters of the above 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 (hereinafter referred to as step 3).

(4) hydrolyzing a (2S, 1'R, 2'S) trans-alcohol ester of the above-obtained loxoprofen (formula 5a) (hereinafter referred to as step 4);

(2S, 1'R, 2'S) trans-alcohol of the following formula (1):

The stereoselective preparation of the Rocorpheoprene (2S, 1'R, 2'S) trans-alcohol is carried out as shown in Reaction Scheme 4 below, and each step will be described in detail.

[Reaction Scheme 4]

Step 1: Synthesis of S- (2S, 1'S) - Compound Containing (2S, 1'S) Ethyl lactate  Preparation of ester mixture

In Step 1, as shown in Reaction Scheme 5 below, acyl halide mixture of formula (3) is prepared by reacting the starting material, Roxsoprofen, of formula (2) with a halogenating agent, which is then concentrated, Dissolve in solvent. (2S, 1'S) - compound of formula (4a) and (2S, 1'S) - compound of formula (4b) can be obtained by reacting with a tertiary amine followed by cooling to -78 to -70 ° C and esterification reaction with S- 2S, 1 ' R) - compounds each of which is at least 40% stereoselectively produced.

[Reaction Scheme 5]

The acyl halide reaction of the loxoprofen can convert an acyl halide mixture of formula (3) by converting a hydroxy group to a halogen group.

The acyl halide reaction can be easily carried out through a generally used halogenating agent. Specifically, the halogenating agent is selected from thionyl chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus pentachloride (PCl ₅ ), phosphorus tribromide (PBr ₃ ), phosphorus pentachloride (PBr ₅ ) ) ₂ ). ≪ / RTI >

The halogenating agent is preferably added in an amount of 1 to 2 equivalents based on 1 equivalent of the Rocopsoprofen of the formula (2), preferably 1 to 1.5 equivalents. When the amount of the halogenating agent is less than 1 equivalent, the acyl halide reaction does not occur and the purity decreases. On the other hand, when the amount of the halogenating agent is more than 2 equivalents, the yield decreases and the manufacturing cost increases.

Thus, an acyl halide mixture of formula (3) can be prepared by adding a halogenating agent to loxoprene and then stirring. In this case, X of formula (III) prepared through the halogenating agent may be chlorine (Cl) or bromine (Br).

The acyl halide mixture of Formula 3 prepared through the halogenating agent is not separately separated, the reaction mixture is cooled to room temperature, concentrated by distillation under reduced pressure, and the solvent is then added to dissolve the concentrated mixture. When the tertiary amine is added in situ to the dissolved solution and the reaction is carried out at room temperature, HX is removed in the acyl halide mixture as shown in Reaction Scheme 6 below, and unstable A ketene intermediate of the following formula (7) is obtained.

[Reaction Scheme 6]

The solvent serves to dissolve the concentrate concentrated by vacuum distillation. The solvent may include at least one selected from the group consisting of toluene, hexane, heptane, and tetrahydrofuran.

The tertiary amine reacts with the halogen of Formula 3 to form a ketene intermediate. The tertiary amine is preferably selected from the group consisting of N -methylpyrrolidine, trimethylamine, dimethylethylamine, diisopropylethylamine, pyridine, picoline, N, N -dimethylaniline, 1,4-diazabicyclo [2.2.2] , Quinuclidine, and quinoline.

The tertiary amine is preferably reacted by adding 1 to 4 equivalents to 1 equivalent of the Rocopsoprene of the formula (2), more preferably 3 to 3.5 equivalents. If the amount of the tertiary amine is less than 1 equivalent, the reaction does not proceed well and the yield of the ketene intermediate may be lowered. If the amount of the tertiary amine is more than 4 equivalents, the production cost may be increased.

At this time, it is preferable that the tertiary amine is dissolved in a solvent such as toluene before being reacted with the acyl halide mixture. The reaction with the tertiary amine can be carried out by stirring at room temperature for 1 hour or more, preferably 2 hours or more.

The ketene intermediate prepared through the reaction with the tertiary amine is highly reactive and unstable, so that the esterification reaction can be carried out directly without separate separation.

The esterification reaction is preferably carried out using S-ethyl lactate (S-ethyl lactate). The reason for this is that stereoselectivity is ensured by using an S-ethyl lactate group, which is a chiral alcohol, to obtain an excess of a (2S, 1'R) - compound having a desired stereo. In particular, since the ester group of formula (5a) can be easily deprotected during the hydrolysis reaction of 4-step to be described later, the reaction can be proceeded even at a low temperature, so that the racemization is minimized.

Therefore, R of the (2S, 1'S) -compound of the formula 4a and the (2S, 1'R) - compound of the formula 4b may be reacted with S-ethyl lactate The

The S-ethyl lactate is preferably added in an amount of 1 to 1.5 equivalents based on 1 equivalent of the Rocopsoprofen of the formula (2), more preferably 1 to 1.3 equivalents. When the amount of the S-ethyl lactate added is less than 1 equivalent, the reaction does not proceed well and the yield of the S-ethyl lactate ester mixture may be lowered. When the amount is more than 1.5 equivalents, the stereoselectivity drops to (2S, 1 < / RTI > R) -compound may be difficult to obtain.

At this time, the esterification reaction is preferably carried out after lowering the temperature to a cryogenic temperature of -78 to -70 占 폚, particularly preferably -78 to -75 占 폚.

(2S, 1 ' R) - (2S, 1'R, 2'S) trans-alcohol having a suitable stereoisomer in the preparation of the loxoprofen (2S, - compounds can be obtained stereoselectively at greater than 40%.

Particularly, when the cooling temperature is higher than -70 ° C, the amount of the (2R, 1'R, 2'S) -epimer which is difficult to remove even by column chromatography increases due to the lack of stereoselectivity and the undesired orientation (2S, 1'R, 2'S) trans-alcohol of the formula (1) to 90% or more.

(2S, 1'S) - compound of the formula (4a) and (2S, 1'R) - compound of the formula (4b) can be obtained by subjecting the reaction mixture obtained by the esterification reaction at the cryogenic temperature to extraction and vacuum distillation, - S-ethyl lactate ester mixture containing the compound can be obtained.

Step 2. Obtaining a mixture of trans-alcohol esters of formulas (5a) and (5b)

In step 2, the S-ethyl lactate ester mixture prepared in step 1 is subjected to a reduction reaction as shown in the following Reaction Scheme 7 and Reaction Scheme 8, and then a cis-ethyl lactate ester mixture of the following formulas (6a) and (6b) Removal of the mixture by column chromatography gives a mixture of trans-alcohol esters of the following 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.

The reduction reaction is preferably a hydride-based reducing agent in order to reduce only the ketone group without reacting with the ester 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 and 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 S-ethyl lactate ester mixture. If the added amount of the reducing agent is out of the above range, the reduction reaction may occur incompletely, and it may be difficult to efficiently reduce the ketone groups of the compounds of the formulas (4a) and (4b).

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, column chromatography can be used to remove the cis-alcohol ester mixture and to easily isolate the trans-alcohol ester mixture.

The reduction reaction with the S-ethyl lactate ester mixture can be carried out by dissolving it in a solvent such as methanol or tetrahydrofuran, and adding a reducing agent.

In addition, the reduction reaction may be carried out under stirring, extraction, concentration under reduced pressure, and separation under cooling conditions.

For example, a reaction solution obtained by adding a solvent to a mixture of S-ethyl lactate ester containing (2S, 1'S) - compound of the formula 4a and (2S, 1'R) Deg.] C, and the mixture is stirred for 30 minutes or more, preferably 1 hour or more.

At this time, the temperature may be elevated to room temperature to allow the reaction to proceed fully, and then the stirring may be carried out for 10 hours or more, preferably 16 hours or more.

Then, when the reaction is completed, the reaction solution is separated into an aqueous layer and an organic layer using water and ethyl acetate, and washed with water or sodium chloride. At this time, it is preferable that the separated aqueous layer is repeatedly extracted and separated using ethyl acetate.

The organic layer of the washed reaction liquid was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of trans-alcohol ester mixture and cis-alcohol ester. The mixture was separated by column chromatography to obtain the oil phase [5a] and [ A trans-alcohol ester mixture of formula (5b) can be obtained.

Step 3. Preparation of Loxophrofen  (2S, 1'R, 2'S) trans-alcohol ester

In Step 3, a trans-alcohol ester mixture of Formula 5a and Formula 5b isolated in Step 2 is reacted with lipase and vinyl acetate as shown in Reaction Scheme 9 below (2S, 1'R, 2'S) trans-alcohol ester of the formula (5a) can be obtained by separation 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 (8). 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 (8) 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).

Amino lipase (Amino Lipase PS) or the like may be used as the lipase. 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) . If the addition amount of the lipase exceeds the above range, the acetylation reaction may incompletely occur and it may be difficult to stereoselectively acetylate the compound of Formula 5b.

In addition, since the acetylated compound [Formula 8] and [Formula 5a] compound have a large R _f difference on thin layer chromatography, they can be easily separated using column chromatography.

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. The acetylation reaction may be carried out at room temperature under stirring, under reduced pressure, and concentration.

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

In step 4, hydrolysis of (2S, 1'R, 2'S) trans-alcohol ester of the loxoprofen (2S, 1'R, 2'S) of the formula 5a isolated in the step 3 as shown in the following reaction scheme [ (2S, 1'R, 2'S) trans-alcohol of formula (1) can be prepared.

[Reaction Scheme 10]

The above-mentioned Reaction Scheme 10 can convert the ester group of the carboxylic acid in the compound of Formula 5a to a hydroxy group by hydrolyzing the trans-alcohol ester compound of Formula 5a.

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

The acid may be an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrogen bromide, or an organic 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 high performance liquid chromatography (HPLC, Agilent 1260). (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 DEG C, a wavelength of 220 nm, and was detected using an ultraviolet detector (UV DETECTOR).

< Example  1> Step 1: Synthesis of S- (2S, 1'R) -containing (2S, 1'S) Ethyl lactate  Ester mixture (R: S- Ethyl lactate group)

(One) Method A (Halogenating agent: Thionyl chloride )

50 g of Loxoprofen was added to the vessel, and dissolved in 400 mL of toluene. Then, 16 mL of thionyl chloride was added thereto at room temperature over 5 minutes in the presence of nitrogen. Then, 1 ml of dimethylformamide was added thereto, and the mixture was stirred at 50 ° C for 3 hours. Then, the mixture was cooled to room temperature, distilled under reduced pressure at 25 DEG C, and concentrated. To the residue was added 400 mL of toluene, and the mixture was concentrated to 1/2. After 200 mL of toluene was added again, a solution of 51 g of N -methylpyrrolidine dissolved in 600 mL of toluene was added over 10 minutes. The mixture was stirred at room temperature for 2 hours, cooled to -78 占 폚, 28.4 g of S-ethyl lactate was added over 20 minutes while maintaining the same temperature, and the mixture was stirred at -78 占 폚 for 1 hour. The reaction mixture was subjected to distillation under reduced pressure, and the residue was separated by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the desired compound (2S, 1'S) '-) - compound was obtained in a yield of 37% as a mixture of S-ethyl lactate esters.

Purity (2S, 1'R-isomer 49.0%, 2S, 1'S-isomer 45.3%, 2R, 1'R-isomer 3.6%, 2R, 1'S- isomer 2.2%

(2) Method B (Halogenating agent: Oxalic chloride )

50 g of loxoprofen was added to the vessel, and dissolved in 400 mL of toluene. Then, 19.2 mL of oxalyl chloride was added in the presence of nitrogen over 5 minutes at room temperature. 0.8 ml of dimethylformamide was added, and the mixture was stirred at 25 占 폚 for 3 hours. Then, the mixture was cooled to room temperature, distilled under reduced pressure at 25 DEG C, and concentrated. To the residue was added 400 mL of toluene, and the mixture was concentrated to 1/2. After 200 mL of toluene was added again, a solution of 51.9 g of N -methylpyrrolidine dissolved in 600 mL of toluene was added over 10 minutes. The mixture was stirred at room temperature for 2 hours, cooled to -78 占 폚, maintained at the same temperature, 28.8 g of S-ethyl lactate was added over 20 minutes, and the mixture was stirred at -78 占 폚 for 1 hour. The reaction mixture was subjected to distillation under reduced pressure, and the residue was separated by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the desired compound (2S, 1'S) (R) - compound was obtained in an amount of 45 g (yield: 64%) as an S-ethyl lactate ester mixture containing the compound.

Purity (2S, 1'R-isomer 48.7%, 2S, 1'S-isomer 46.5%, 2R, 1'R-isomer 2.7%, 2R,

< Example  2> Step 2. A mixture of trans-alcohol esters (R: S-ethyl lactate group) of the formulas (5a) and (5b)

To the vessel was added 17.2 g of the S-ethyl lactate ester mixture prepared in Method A of Example 1, dissolved in 170 mL of tetrahydrofuran, and then 28.4 mL of acetic acid was added while maintaining the temperature at 20 to 25 캜. Then, after cooling to 0 ° C, 4.7g of sodium borohydride (NaBH ₄ ) was slowly added maintaining the copper temperature. The reaction solution was then stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred overnight. 100 mL of water and 130 mL of ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated. The aqueous layer was extracted again with 30 mL of ethyl acetate, and then the whole was combined. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain the cis-alcohol ester of the formula 6a and 6b The mixture was removed to obtain 5.6 g (yield: 33%) of a mixture of trans-alcohol esters of the formula [5a] and [formula 5b] as target compounds on the oil phase.

Purity (2S, 1'R, 2'S-isomer 47.0%, 2S, 1'S, 2'R-isomer 48.9%)

< Example  3> Step 3. A compound of the formula Loxophrofen  (2S, 1'R, 2'S) trans-alcohol ester (R: S- Ethyl lactate group )

28 g of the trans-alcohol ester mixture of the formulas (5a) and (5b) prepared in Example 2 was added to the container and dissolved in 85 ml of toluene. Then 3.1 g of Amanoripase PS, 3.1 g of molecular sieves 3A powder and 22 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) to obtain the desired compound of the formula (5a) 2S, 1'R, 2'S) trans-alcohol ester (yield: 43%).

Purity (2S, 1'R, 2'S-isomer 94.9%, 2R, 1'R, 2'S-isomer 3.0%)

< Example  4> Step 4. A compound of formula Loxophrofen  (2S, 1'R, 2'S) trans-alcohol production

To the container was added 2.4 g of the trans-alcohol ester compound of the formula (5a) prepared in Example 3, and dissolved in 24 ml of acetonitrile. Then, the solution was cooled to about 0 ° C, and an aqueous solution prepared by dissolving 1.5 g of lithium hydroxide monohydrate (LiOH.H ₂ O) in 24 mL of water was slowly added to the solution while maintaining the temperature at about 0 ° C., Respectively. 48 mL of ethyl acetate was then added and extracted with 48 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 24 mL of dichloromethane, and dried over anhydrous magnesium sulfate. The dried reaction solution was filtered, concentrated under reduced pressure, and dissolved in 5 mL of ethyl acetate. Subsequently, 32 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 1.4 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 92.2%, 2R, 1'R, 2'S-isomer (epimer) 7.7%

_{^{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)

(2S, 1'R, 2'S) trans-alcohol of Formula 1 of Example 4, which was prepared through Examples 1-4 of the present invention, It can be seen that the yield is 85% or more and the purity is 90% or more. 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 (12)

(1) reacting Roxsoprofen of the following formula (2) with a halogenating agent to obtain an acyl halide mixture of the following formula (3), concentrating the resulting mixture, dissolving the concentrate in a solvent, (2S, 1S) - compound of the following formula (4a) and (2S, 1S) - compound of the formula (4b) by reacting with a tertiary amine, 1 ' R) -compound, each containing at least 40% of the S-ethyl lactate ester mixture,
(2) The S-ethyl lactate ester mixture prepared above is subjected to a reduction reaction, and then the cis-mixture of the following formulas (6a) and (6b) is removed by column chromatography to obtain the following formula (5a) Of a trans-alcohol ester mixture,
(3) A mixture of trans-alcohol esters of the above 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
(4) hydrolyzing the (2S, 1'R, 2'S) trans-alcohol ester of the loxoprofen of formula (5a) obtained above to form a stereoselective loxoprofen (2S, 1'R, 2'S) trans-alcohol:
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

X is Cl or Br, and R is S-ethyl lactate in the formulas 4a, 4b, 5a, 5b, 6a and 6b.
The method according to claim 1,
The halogenating agent consisting of thionyl chloride (SOCl _2), phosphorus trichloride (PCl _3), phosphorus pentachloride (PCl _5), save phosphorus tribromide (PBr _3), five bromide in (PBr ₅₎ and yeomhwaok (COCl) ₂ (2S, 1 ' R, 2 ' S) trans-alcohols.
The method of claim 2,
(2S, 1'R, 2'S) trans-alcohol in which 1 to 2 equivalents of the halogenating agent is added in an amount of 1 to 2 equivalents based on 1 equivalent of the Rocopsoprofen of the formula (2) Way.
The method according to claim 1,
Wherein the solvent comprises at least one selected from the group consisting of toluene, hexane, heptane and tetrahydrofuran. 2. The process according to claim 1, wherein the solvent is at least one selected from the group consisting of toluene, hexane, heptane and tetrahydrofuran.
The method according to claim 1,
The tertiary amine is preferably selected from the group consisting of N -methylpyrrolidine, trimethylamine, dimethylethylamine, diisopropylethylamine, pyridine, picoline, N, N -dimethylaniline, 1,4-diazabicyclo [2.2.2] (2S, 1'R, 2'S) trans-alcohol, characterized in that it comprises at least one selected from the group consisting of quinuclidine and quinoline.
The method of claim 5,
(2S, 1'R, 2'S) trans-alcohol of the stereoselective oxazolidine, wherein the tertiary amine is reacted by adding 1 to 4 equivalents based on 1 equivalent of Rocopsoprofen of the formula (2) Gt;
The method according to claim 1,
(2S, 1'R, 2'S) trans-alcohol, characterized in that the cooling is carried out at a temperature of from -78 to -75 ° C.
The method according to claim 1,
(2S, 1'R, 2'S) trans-S-ethyl lactate is reacted by adding 1 to 1.5 equivalents of the S-ethyl lactate to 1 equivalent of Rocopsoprofen of the formula (2) A method for producing an 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. 'R, 2'S) trans-alcohol.
The method of claim 9,
(2S, 1'R, 2'S) trans-alcohol is reacted by adding 1 to 3 equivalents of the reducing agent to 1 equivalent of the S-ethyl lactate ester mixture.
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 formula (1).
The method according to any one of claims 1 to 11,
(2S, 1'R, 2'S) trans-alcohol having a purity of 90% or more.