KR101198657B1

KR101198657B1 - Method for preparing optically active 2-arylpropionic acid drugs using S-+-1-aminoindan

Info

Publication number: KR101198657B1
Application number: KR20100080020A
Authority: KR
Inventors: 이기철
Original assignee: 주식회사 제이팜
Priority date: 2010-08-18
Filing date: 2010-08-18
Publication date: 2012-11-12
Also published as: KR20120017367A

Abstract

The present invention relates to a method for preparing a (S) -2-arylpropionic acid-based drug having high yield and high purity optical activity:
2-arylpropionic acid and (S)-(+)-1-aminoindan containing an excess of racemic or S isomers are dissolved in a polar solvent, heated and cooled, and then cooled to (S) -2-arylpropionic acid-. Preparing (S)-(+)-1-aminoindane salt into crystals (step 1); And (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt, adding an aqueous inorganic acid solution and an organic solvent to extract (S) -2-arylpropionic acid as an organic solvent layer, and then Concentrating the solvent layer under reduced pressure to prepare (S) -2-arylpropionic acid (step 2-1) or the isolated (S) -2-arylpropionic acid-(S)-(+)-1-aminoindane salt It is characterized in that it comprises a; (2) step of preparing a (S) -2-arylpropionic acid by filtering the precipitate produced by adding an inorganic acid aqueous solution to.
According to the present invention, a pharmaceutically useful (S) -isomer 2-arylpropionic acid-based drug can be obtained in high purity and high yield, and furthermore, through a simple manufacturing process, the used splitting agent can be easily recovered and reused. Can be.

Description

Method for preparing optically active 2-arylpropionic acid drugs using (S)-(+)-1-aminoindan (S)-(+)-1-aminoindan }

The present invention relates to a method for preparing a 2-arylpropionic acid-based drug (Ibuprofen, Naproxen, Ketoprofen, Zaltoprofen, Flubiprofen, Phenopropene, etc.) having optical activity.

In more detail, the present invention relates to a method for preparing a 2-arylpropionic acid-based drug which can obtain (S) -isomer pharmaceutically useful from racemic 2-arylpropionic acid-based drug in high yield and high purity.

2- (4-isobutylphenyl) propionic acid of Formula 1, commonly referred to as ibuprofen, 2- (6-meth) of Formula 2, referred to as naproxen 2- (6-methoxy naphthalen-2-yl) propionic acid, 2- (3-benzoylphenyl) propionic acid of the formula (3) called ketoprofen 3-benzoylphenyl) propionic acid), 2- (10,11-dihydro-10-oxodibenzo [b, f] thiin-2-yl) propionic acid (2), referred to as Zaltoprofen -(10,11-Dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid), 2- (2-fluorobiphenyl-4), referred to as Flurbiprofen 2- (2- (2-fluorobiphenyl-4-yl) propionic acid), 2- (4-phenoxyphenyl) propionic acid (2- (4-phenoxyphenyl) propionic acid) is an anti-inflammatory, antipyretic and analgesic As a medicine having the effect, in particular, widely used in the treatment of pain and treatment of headache, neuralgia of infection in musculoskeletal disorders such as rheumatic disease.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

Generally, 2-arylpropionic acid-based drugs (Ibuprofen, Naproxen, Ketoprofen, Zaltoprofen, Flurbiprofen, Phenopropene, etc.) have been used in the form of racemic mixtures. With the recent discovery that only the) -isomer has medicinal activity and the (R) -isomer is inactive, the 2-arylpropionic acid class drugs (ibuprofen, naproxen, ketoprofen, zaltoprofen, flurbipro There is a need for a method of isolating and producing the (S) -isomer from the racemic mixture of pens, phenopropenes, and the like.

Conventionally, the conventional method for separating and preparing the (S) -isomer from a racemic mixture of 2-arylpropionic acid-based drugs is as follows.

U.S. Patent No. 5,015,764 discloses a process for separating racemic mixtures of aliphatic carboxylic acids, including ibuprofen, naproxen, and flurbiprofen, using chiral methylbenzylamine as a splitting agent, but the process is performed seven times. The above recrystallization must be carried out to obtain a high purity propene drug, which has a disadvantage in that the yield is very low.

Korean Patent No. 280,766 discloses a method for separating optically active compounds such as ibuprofen and flurbiprofen using chiral methylbenzylamine as a dividing agent, but to obtain high purity (S) -ibuprofen, chiral methyl of ibuprofen The disadvantage is that the benzylamine salt has to be recrystallized over seven times.

U.S. Patent No. 4,994,604 discloses a method for separating (S) -ibuprofen by using (S) -lysine, which is a kind of amino acid, as a splitting agent, but the recovery of lysine is very difficult.

U.S. Patent No. 5,162,576 discloses a method for separating optically active (S) -ketoprofen from racemic ketoprofen, wherein a splitting agent, cinchonidine, is reacted on an organic solvent. The method does not disclose a method for recovering used cicononidine.

In addition, Korean Patent Publication No. 2003-2955 discloses (S) -Ibuprofen-N in a polar solvent by using N-octyl-D-glucamine in a polar solvent, using 0.45 equivalents to ibuprofen. A method for separating (S) -ibuprofen by forming an octyl-D-glucamine salt is disclosed. This method not only uses N-octyl-D-glucamine, which is a non-toxic solid and easy to reuse, but also has the advantage of separating almost pure (S)-ibuprofen in a single process, but (S)-ibuprofen- Since N-octyl-D-glucamine salt is substantially dissolved in a polar solvent such as ethanol containing water, the yield in terms of N-octyl-D-glucamine used is only about 75 to 80%. The recovery process is complicated.

An object of the present invention is a 2-aryl (S) -isomer from a racemic 2-arylpropionic acid-based drug (Ibuprofen, Naproxen, Ketoprofen, Zaltoprofen, Flubiprofen, Phenopropene, etc.). It is to provide a method for producing a propionic acid-based drug in high purity and high yield.

Still another object of the present invention is to provide a resolving agent which is simple in its manufacturing process, after separating the (S) -isomer 2-arylpropionic acid-based drug from the racemic 2-arylpropionic acid-based drug. It is to provide a method for preparing a (S) -2-arylpropionic acid-based drug having an optical activity with improved economic efficiency by allowing easy recovery and reuse.

In order to achieve this object, the present invention provides a method for preparing (S) -2-arylpropionic acid having high yield and high purity optical activity, comprising the following steps:

(a) dissolving (S)-(+)-1-aminoindan ((S)-(+)-1-aminoindan) in a polar solvent with a 2-arylpropionic acid containing excess of racemic or S isomers and a splitting agent; After the reaction, the mixture is heated and cooled to prepare (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt as crystals (step 1); And

(b-1) An aqueous inorganic acid solution and an organic solvent are added to the isolated (S) -2-arylpropionic acid- (S)-(+)-1-aminoindan salt to form (S) -2-arylpropionic acid as an organic solvent layer. Extraction and then concentration of the organic solvent layer under reduced pressure to produce (S) -2-arylpropionic acid (step 2-1).

According to another aspect of the present invention, there is provided a method for preparing (S) -2-arylpropionic acid having high yield and high purity optical activity, comprising the following steps:

(A) (S)-(+)-1-aminoindan is dissolved in a polar solvent with 2-arylpropionic acid containing an excess of racemic or S isomers and a splitting agent, and then heated and cooled to (S)- Preparing a 2-arylpropionic acid- (S)-(+)-1-aminoindane salt as a crystal (step 1); And

(b-2) To the isolated (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt, an aqueous solution of inorganic acid was added to make acidic (pH 5 or less), followed by filtration (S)- Step of preparing 2-arylpropionic acid (step 2-2).

According to another aspect of the present invention, after the step 2-1 or step 2-2, including (S) -2-arylpropionic acid having high yield and high purity optical activity, including the following additional steps Provide the method:

(c) adding an inorganic base aqueous solution and an organic solvent to the inorganic acid aqueous solution layer of step 2-1 or step 2-2, extracting (S)-(+)-1-aminoindan into the organic solvent layer and concentrating under reduced pressure (S) )-(+)-1-aminoindane is obtained (3 steps).

In addition, according to another aspect of the present invention, (d) by treating the inorganic acid from the residue obtained by concentrating the filtrate obtained in the step 1 to obtain 2-arylpropionic acid containing excess of the (R) isomer, and then basified again ( It provides a method of producing (S) -2-arylpropionic acid having high yield and high purity optical activity further comprising the step (4 step) of obtaining S)-(+)-1-aminoindan.

Hereinafter, the present invention will be described in more detail.

Step (a): Racemic 2- Arylpropionic acid (S)-(+)-1- Amino indane By reaction (S) -2-a Rilpro Pionic Acid- (S)-(+)-1- Aminoindan Salt manufacture

As a first step of the present invention, 2-arylpropionic acid and (S)-(+)-1-aminoindan, which contain an excess of racemic or S isomers, are dissolved in a polar solvent, heat-reacted and then cooled ( S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt is prepared as crystals.

In the production method of the present invention, 2-arylpropionic acid used as a starting material is a racemic mixture of 2-arylpropionic acid or a mixture containing an excess of S isomer. Thus, using the above-described method of the present invention, pharmaceutically useful (S) -isomers can be produced at low cost from racemic mixtures of conventional 2-propionic acid based drugs.

In addition, as the 2-arylpropionic acid of the present invention, any one selected from the group consisting of ibuprofen, naproxen, ketoprofen, zaltoprofen, flurbiprofen, and phenopropene is used.

In the production method of the present invention, (S)-(+)-1-aminoindane used as the dividing agent is a chiral methylbenzylamine, N-octyl-D-glucamine salt, (S)- Unlike lysine or cinchonidine, the conformation is fixed, and thus, there is an advantage that crystals are easily formed by forming a very stable salt with 2-arylpropionic acids. Therefore, the present invention provides a pharmaceutical composition at a lower cost than the conventional manufacturing method by separating the (S) -isomer of the 2-arylpropionic acid-based drug using (S)-(+)-1-aminoindane as a dividing agent. Useful 2-arylpropionic acid based drugs can be prepared in high yield and high purity, improving the economics of the overall process.

As the polar solvent used in the step (a) of the present invention, a solvent selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, a mixed solvent of the lower alcohols and water, and acetonitrile is suitably used, and most preferably , Solvents selected from the group consisting of methanol, ethanol, a mixture of methanol and water, a mixture of ethanol and water, isopropanol and acetonitrile are used.

In addition, in step (a) of the present invention, the amount of the 2-arylpropionic acid-based drug and (S)-(+)-1-aminoindan is preferably controlled in a molar ratio. According to a preferred embodiment of the present invention, the molar ratio of the 2-arylpropionic acid-based drug to (S)-(+)-1-aminoindan is preferably 1 to 0.4 to 2, more preferably 1 to 0.5 to 1.5, most preferably 1 to 0.5 to 1.

As described above, 2-arylpropionic acid and (S)-(+)-1-aminoindan are added to the polar solvent and reacted to form (S)-(+ of the 2-arylpropionic acid-based drug having the structure of the (S) -isomer. Allow to produce) -1-aminoindane salt, and then heat and cool to recrystallize (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt.

The heating temperature is performed in a temperature range in which a solution containing a salt of a 2-arylpropionic acid-based drug can form a supersaturated solution, preferably 40 ° C. to 90 ° C., and more preferably 60 ° C. to 90 ° C. . After heating, it is cooled to a temperature at which the salt of the 2-arylphthalic acid series drug can be precipitated by recrystallization, preferably to a temperature of 0 to 30 ° C.

By cooling as described above, the salt crystal of the 2-arylpropionic acid-based drug having the structure of the (S) -isomer is immediately filtered, and the precipitate is separated from the filtrate separately, the precipitate is dried and the filtrate is distilled under reduced pressure.

Step (b-1) and Step (b-2): (S) -2- Arylpropionic acid purchase

In the step (b-1) of the present invention, an aqueous inorganic acid solution and an organic solvent are added to the (S)-(+)-1-aminoindane salt of the 2-arylpropionic acid of (S) -isomer separated in the step (a). After addition, the 2-arylpropionic acid-based drug of the (S) -isomer is extracted into the organic solvent layer, and then the organic solvent layer is concentrated under reduced pressure to obtain the 2-arylpropionic acid-based drug of the (S) -isomer.

Alternatively, according to another embodiment of the present invention, as (b-2), (S)-(+)-1-amino of the (S) -isomer 2-arylpropionic acid-based drug separated in the step (a) An aqueous inorganic acid solution is added to the phosphorus salt to obtain a 2-arylpropionic acid-based drug of the (S) -isomer precipitated.

As the inorganic acid solution, an inorganic acid solution used in the art may be used, more preferably hydrochloric acid, sulfuric acid, or nitric acid is used, and most preferably hydrochloric acid is used.

In addition, as the organic solvent, preferably a nonpolar solvent is used, more preferably dichloromethane, n-heptane, ethyl ether, benzene, toluene, ethyl acetate, chloroform, or dichloroethane, most preferably Dichloromethane is used.

The 2-arylpropionic acid-based drug crystal of the (S) -isomer obtained as described above is filtered, washed as necessary, and dried to obtain a high purity (S) -isomer 2-arylpropionic acid-based drug crystal.

Step (c): (S)-(+)-1- Aminoindan collection

To the inorganic acid aqueous solution layer of step (b-1) or (b-2), an inorganic base is added to give a basic pH of 11 or more, and an organic solvent is added to (S)-(+)-1-aminoindan Extracted with an organic solvent layer, and then concentrated under reduced pressure.

As the inorganic base, inorganic bases used in the art may be used, and preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, or calcium hydroxide is used.

In addition, as the organic solvent used in step (c) of the present invention, a nonpolar solvent is preferably used, and more preferably dichloromethane, n-heptane, pentane, ethyl ether, benzene, toluene, or chloroform is used. Most preferably dichloromethane is used.

Step (d): (S)-(+)-1- from the filtrate obtained in step (a) Aminoindan collection

According to another aspect of the present invention, as step (d), the residue obtained by concentrating the filtrate obtained in step (a) is basified with an inorganic base to pH 11 or more, and an organic solvent is added to (S)-( +)-1-amine indan may be recovered. As the inorganic base and the organic solvent used in the step (d), the inorganic base and the organic solvent used in the step (c) are used.

According to the preparation method of the present invention, a (S) -isomer 2-arylpropionic acid-based drug having a pharmaceutically useful activity can be obtained in high purity and high yield from a racemic mixture of a conventionally commercially available 2-arylpropionic acid-based drug. have.

In addition, the manufacturing method of the present invention is not only a simple manufacturing process, but also easy to recover and reuse the splitting agent used in the process, it is a pharmaceutically useful (S) -isomer 2-arylpropionic acid series The drug can be prepared at low cost, thereby improving the economics of the entire process.

Hereinafter, the present invention will be described in detail through preferred embodiments. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

< Example 1: (S)-(+)-1- Amino indane using Racemic (S) -Ibuprofen Preparation from Ibuprofen>

A. Racemic (S) -Ibuprofen- (S)-(+)-1- from ibuprofen Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of ibuprofen and (S)-(+)-1-aminoindane (6.3 g (0.5 equiv. ), Or 8.8 g (0.7 equiv), or 12.5 g (1 equiv) was added dropwise and then heated to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 10 to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Repeat the recrystallization three times to obtain (S) -Ibuprofen- (S)-(+)-1-aminoindone salt. Take a small sample and analyze by HPLC to confirm that it shows satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain high purity (S)-ibuprofen- (S)-(+)-1-aminoindadan salt.

B-1. (S) -Ibuprofen- (S)-(+)-1- From aminoindan salts Preparation of (S) -Ibuprofen

In the reactor, (S) -Ibuprofen- (S)-(+)-1-aminoindone salt was dissolved in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water, and the organic layer was dehydrated with anhydrous forget-me-not. It concentrated under reduced pressure, and obtained white (S)-ibuprofen.

NaOH was added dropwise to the water layer of the reaction to make a basic solution (pH 11 or more), and then dissolved in 100 ml of dichloromethane. The extracted organic layer was washed three times with 100 ml of distilled water. -(+)-1-aminoindan was obtained.

C. Purity Analysis

Sample: isopropanol solution

Column: CHIRALCEL OD-H, 5 um (4.6 mm x 250 mm)

Solvent: n-hexane / Isopropanol / TFA = 90/1 / 0.1 (ｖ / ｖ)

Flow rate: 1 ml / min

-Detector: Tunable Absorbance Detector, UV 254 nm

Injection volume: 10 μl

According to the reaction solvent when preparing (S) -Ibuprofen- (S)-(+)-1-aminoindane salt from racemic ibuprofen, the yield and optical activity ratio of the prepared (S) -ibuprofen are shown in [Table 1]. Indicated.

menstruum
Split amount equivalent

Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 4.63 23.2 99.13 0.87 0.7 5.08 25.4 98.72 1.28 1.0 4.82 24.1 99.52 0.48
80% methanol 0.5 4.59 23.0 99.54 0.46 0.7 5.05 25.3 98.93 1.07 1.0 5.21 26.1 98.62 1.38
ethanol 0.5 5.27 26.4 99.22 0.78 0.7 5.44 27.2 98.69 1.31 1.0 5.82 29.1 99.55 0.45
70% ethanol 0.5 4.38 21.9 99.05 0.95 0.7 5.31 26.6 99.57 0.43 1.0 4.92 24.6 98.57 1.43
Isopropanol 0.5 4.86 24.3 99.04 0.96 0.7 5.04 25.2 98.58 1.42 1.0 4.47 22.4 99.06 0.94
Acetonitrile 0.5 4.08 20.4 99.34 0.66 0.7 4.25 21.3 98.96 1.04 1.0 4.18 20.9 98.59 1.41

D. Recovery of Ibuprofen and Splitter from the Filtrate

The filtrate obtained in step A was concentrated to dissolve ibuprofen- (S)-(+)-1-aminoindadan salt with excessive (R) -isomer in 100 ml of 1N-HCl and 100 ml of dichloromethane, and extracted organic layer with 100 ml of distilled water. After washing three times, the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a white ibuprofen.

NaOH was added dropwise to the water layer of the reaction to make a basic solution (pH 11 or more), and then dissolved in 100 ml of dichloromethane. The extracted organic layer was washed three times with 100 ml of distilled water. -(+)-1-aminoindan salt was obtained. The yield of (S)-(+)-1-aminoindan salt obtained in step B-1 and recovered in this step was 99% or more.

< Example 2: (S)-(+)-1- Amino indane using Racemic From ketoprofen (S) -ke Toffee Lofen manufacturing>

A. Racemic From ketoprofen (S) - Ketoprofen -(S)-(+)-1- Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of ketoprofen and (S)-(+)-1-aminoindane (5.2 g ( 0.5 equivalent), or 7.3 g (0.7 equivalent), or 10.4 g (1.0 equivalent)) was added dropwise and then heated to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 10 to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Repeat the recrystallization three times to obtain (S) -ketoprofen- (S)-(+)-1-aminoindane salt, take a small sample and analyze by HPLC to confirm that it shows satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -ketopropene- (S)-(+)-1-aminoindane salt.

B-1. Preparation of (S) -ketoprofen from (S) -ketoprofen- (S)-(+)-1-aminoindane salt

After dissolving (S) -ketopropene- (S)-(+)-1-aminoindan salt in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water and the organic layer was dried The mixture was dehydrated and concentrated under reduced pressure to obtain a white (S) -ketopropene.

C. Purity Check

Sample: isopropanol solution

Column: CHIRALPAK AD-H, 5 um (4.6 mm x 250 mm)

Solvent: n-hexane / Isopropanol / TFA = 90/10 / 0.1 (ｖ / ｖ)

Flow rate: 1 ml / min

-Detector: Tunable Absorbance Detector, UV 254 nm

Injection volume: 10 μl

Yield and optical activity ratio of (S) -ketoprofen prepared according to the reaction solvent in preparing (S) -ketoprofen- (S)-(+)-1-aminoindane salt from racemic ketoprofen It is shown in [Table 2].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 4.33 21.7 99.80 0.20 0.7 4.94 24.7 99.15 0.85 1.0 5.47 27.4 98.53 1.47
80% methanol 0.5 4.80 24.0 98.73 1.27 0.7 4.51 22.6 99.59 0.41 1.0 4.84 24.2 99.25 0.75
ethanol 0.5 4.29 21.5 99.24 0.76 0.7 5.88 29.4 98.74 1.26 1.0 6.02 30.1 98.81 1.19
70% ethanol 0.5 4.46 22.3 98.33 1.67 0.7 5.21 26.1 98.06 1.94 1.0 5.08 25.4 99.58 0.42
Isopropanol 0.5 4.14 20.7 98.01 1.99 0.7 4.91 24.6 98.84 1.16 1.0 5.27 26.4 99.09 0.91
Acetonitrile 0.5 4.11 20.6 99.75 0.25 0.7 4.96 24.8 98.26 1.74 1.0 4.92 24.6 99.05 0.95

< Example 3 :. (S)-(+)-1- Amino indane using Racemic From zaltoprofen (S) -well Toffee Lofen manufacturing>

A. Racemic From zaltoprofen (S) - Zaltoprofen -(S)-(+)-1- Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and as a reactant, 20.0 g of zaltoprofen and (S)-(+)-1-aminoindane (4.5 g ( 0.5 equivalent), or 6.2 g (0.7 equivalent), or 8.9 g (1.0 equivalent)) was added dropwise and then heated to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 10 to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated three times to obtain (S) -saltoprofen- (S)-(+)-1-aminoindane salt, and a small amount of samples were taken and analyzed by HPLC to ensure satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -saltoprofen- (S)-(+)-1-aminoindane salt.

B-1. (S) - Zaltoprofen -(S)-(+)-1- Aminoindan From salt (S)- Of saltoprofen Produce

After dissolving (S) -zaltoprofen- (S)-(+)-1-aminoindan salt in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water and the organic layer was dried The mixture was dehydrated and concentrated under reduced pressure to obtain a white (S) -saltopropene.

C. Purity Check

Sample: isopropanol solution

Column: CHIRALCEL OJ-H, 5 um (4.6 mm x 250 mm)

Solvent: n-hexane / Isopropanol / TFA = 95/5 / 0.1 (ｖ / ｖ)

Flow rate: 0.5 ml / min

-Detector: Tunable Absorbance Detector, UV 254 nm

Injection volume: 10 μl

Yield and optical activity ratio of (S) -zaltoprofen prepared according to the reaction solvent when preparing (S) -saltoprofen- (S)-(+)-1-aminoindane salt from racemic zaltoprofen It is shown in [Table 3].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 5.49 27.5 99.70 0.30 0.7 5.70 28.5 99.49 0.51 1.0 6.22 31.1 99.01 0.99
80% methanol 0.5 4.31 21.6 99.38 0.62 0.7 4.56 22.8 98.55 1.45 1.0 4.29 21.5 99.00 1.00
ethanol 0.5 5.08 25.4 98.83 1.17 0.7 5.94 29.7 98.71 1.29 1.0 5.63 28.2 98.57 1.43
70% ethanol 0.5 4.55 22.8 98.53 1.47 0.7 4.52 22.6 99.08 0.92 1.0 4.94 24.7 99.53 0.47
Isopropanol 0.5 4.16 20.8 98.54 1.46 0.7 4.73 23.7 99.11 0.89 1.0 5.26 26.3 98.77 1.23
Acetonitrile 0.5 4.91 24.6 98.64 1.36 0.7 4.88 24.4 98.57 1.43 1.0 5.70 28.5 99.02 0.98

< Example 4: (S)-(+)-1- Amino indane using Racemic From flurbiprofen (S) -Flubiprofen preparation>

A. Racemic From flurbiprofen (S) - Flulubiprofen -(S)-(+)-1- Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of flurbiprofen and (S)-(+)-1-aminoindane (5.5 g (0.5 equiv), or 7.6 g (0.7 equiv), or 10.9 g (1.0 equiv) was added dropwise and then heated to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 10 to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Repeat the recrystallization three times to obtain (S) -Flurbiprofen- (S)-(+)-1-aminoindane salt, take a small sample and analyze by HPLC to confirm that it shows satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -flubiprofen- (S)-(+)-1-aminoindane salt.

B-1. Preparation of (S) -Flubiprofen from (S) -Flubiprofen- (S)-(+)-1-aminoindane salt

After dissolving (S) -Flubiprofen- (S)-(+)-1-aminoindone salt in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water and the organic layer was Dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain white (S) -flubiprofen.

C. Purity Analysis

Sample: isopropanol solution

Column: CHIRALPAK AD-RH, 5 um (4.6 mm x 150 mm)

Solvent: H ₃ PO ₄ (1%) / CH ₃ CN = 50:50 （ｖ / ｖ）

Flow rate: 1 ml / min

-Detector: UV-VIS Detector, UV 254 nm

Injection volume: 10 μl

Yield of (S) -Flubiprofen prepared according to the reaction solvent in the preparation of (S) -Flubiprofen- (S)-(+)-1-aminoindane salt from racemic flubiprofen And optical activity ratio results are shown in [Table 4].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 4.98 24.9 98.06 1.94 0.7 4.21 21.1 99.53 0.47 1.0 4.67 23.4 99.31 0.69
80% methanol 0.5 5.29 26.5 99.08 0.92 0.7 5.15 25.8 98.87 1.13 1.0 5.71 28.6 99.52 0.48
ethanol 0.5 5.86 29.3 98.57 1.43 0.7 4.95 24.8 99.58 0.42 1.0 5.29 26.5 98.76 1.24
70% ethanol 0.5 4.80 24.0 98.78 1.22 0.7 4.57 22.9 99.50 0.50 1.0 5.82 29.1 98.54 1.46
Isopropanol 0.5 4.02 20.1 98.88 1.12 0.7 5.03 25.2 98.27 1.73 1.0 4.93 24.7 98.82 1.18
Acetonitrile 0.5 4.89 24.5 99.07 0.93 0.7 5.18 25.9 98.66 1.34 1.0 5.26 26.3 98.21 1.79

< Example 5: (S)-(+)-1- Amino indane using Racemic (S) -naproxen production from naproxen>

A. Racemic From naproxen (S) -naproxen- (S)-(+)-1- Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of naproxen and (S)-(+)-1-aminoindane (5.6 g (0.5 equiv. ), Or 8.1 g (0.7 equiv), or 11.6 g (1.0 equiv)) was added dropwise and then heated to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 10 to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization is repeated three times to obtain (S) -naproxen- (S)-(+)-1-aminoindane salt, and a small sample is taken and analyzed by HPLC to ensure satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -naproxen- (S)-(+)-1-aminoindane salt.

B-1. (S) -naproxen- (S)-(+)-1- Aminoindan Preparation of (S) -naproxen from salt

After dissolving (S) -naproxen- (S)-(+)-1-aminoindone salt in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water and the organic layer was dehydrated with anhydrous forget-me-not. It concentrated under reduced pressure, and obtained white (S) -naproxen.

C. Purity Analysis

_ Sample: isopropanol solution

Column: CHIRALCEL OD-H, 5 um (4.6 mm x 250 mm)

Solvent: n-hexane / Isopropanol / TFA = 96/4 / 0.1 (ｖ / ｖ)

Flow rate: 1 ml / min

-Detector: Tunable Absorbance Detector, UV 210 nm

Injection volume: 5 μl

The yield and optical activity ratio of (S) -naproxen prepared according to the reaction solvent when preparing (S) -naproxen- (S)-(+)-1-aminoindane salt from racemic naproxen are shown in [Table 5]. It was.

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 4.33 21.7 99.52 0.48 0.7 4.84 24.2 98.47 1.53 1.0 4.91 24.6 98.92 1.08
80% methanol 0.5 5.28 26.4 99.45 0.55 0.7 4.90 24.5 99.78 0.22 1.0 6.22 31.1 98.47 1.53
ethanol 0.5 6.42 32.1 98.60 1.40 0.7 6.03 30.2 99.05 0.95 1.0 5.86 29.3 99.58 0.42
70% ethanol 0.5 5.30 26.5 98.45 1.55 0.7 5.81 29.1 98.08 1.92 1.0 5.44 27.2 99.01 0.99
Isopropanol 0.5 5.17 25.9 98.76 1.24 0.7 5.08 25.4 98.44 1.56 1.0 4.79 24.0 99.52 0.48
Acetonitrile 0.5 4.67 23.4 98.79 1.21 0.7 4.66 23.3 99.01 0.99 1.0 5.93 29.7 98.63 1.37

< Example 6: (S)-(+)-1- Amino indane using Racemic From phenopropene (S) -fe Nov Lofen manufacturing>

A. Racemic From phenopropene (S) - Phenopropene -(S)-(+)-1- Aminoindan Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of phenopropene and (S)-(+)-1-aminoindane (5.5 g) as reactants. (0.5 equiv), or 7.7 g (0.7 equiv), or 11.0 g (1.0 equiv) was added drop wise and then heated to 80 ° C. to completely dissolve the reaction The reaction was cooled to 10-25 ° C. for 1 hour When left to recrystallize and filtered, the precipitate was separated from the filtrate separately, the precipitate was dried and the filtrate was distilled under reduced pressure.The recrystallization was repeated three times (S) -phenopropene- (S)-(+ Obtain 1-1-aminoindane salt, take a small amount of sample and analyze it by HPLC to see if it shows satisfactory purity, and if it is not satisfactory, perform recrystallization once more to obtain high-purity (S) -phenopropene. -(S)-(+)-1-aminoindane salt was obtained.

B-1. (S) - Phenopropene -(S)-(+)-1- Aminoindan From salt (S)- Phenopropene Produce

After dissolving (S) -phenopropene- (S)-(+)-1-aminoindone salt in 100 ml of 1N-HCl and 100 ml of dichloromethane, the extracted organic layer was washed three times with 100 ml of distilled water and the organic layer was dried anhydrous. Dehydrated with forget-me-not and concentrated under reduced pressure to obtain a white (S) -phenopropene.

C. Purity Analysis

Sample: isopropanol solution

Column: CHIRALCEL OJ-H, 5 um (4.6 mm x 250 mm)

Solvent: n-hexane / Isopropanol / TFA = 90/10 / 0.05 (ｖ / ｖ)

Flow rate: 1 ml / min

-Detector: Tunable Absorbance Detector, UV 210 nm

Injection volume: 5 μl

Yield and Optical Activity of (S) -phenopropene Prepared according to Reaction Solvent in Preparation of (S) -phenopropene- (S)-(+)-1-aminoindane Salt from Racemic Phenopropene The ratio results are shown in [Table 6].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol 0.5 4.38 21.9 98.52 1.48 0.7 5.20 26.0 99.04 0.96 1.0 4.91 24.6 99.53 0.47
80% methanol 0.5 5.39 27.0 99.00 1.00 0.7 4.84 24.2 99.63 0.37 1.0 5.68 28.4 99.32 0.68
ethanol 0.5 5.31 26.6 98.06 1.94 0.7 4.76 23.8 99.52 0.48 1.0 5.81 29.1 98.49 1.51
70% ethanol 0.5 4.99 25.0 98.53 1.47 0.7 5.83 29.2 99.50 0.50 1.0 6.37 31.9 99.04 0.96
Isopropanol 0.5 6.38 31.0 98.64 1.36 0.7 5.46 27.3 98.62 1.38 1.0 5.90 29.5 99.05 0.95
Acetonitrile 0.5 5.08 25.4 98.53 1.47 0.7 5.75 28.8 99.52 0.48 1.0 5.81 29.1 99.05 0.95

< Example 7: (S)-(+)-1- Amino indane using Racemic (S) -Ibuprofen Preparation from Ibuprofen>

A. Racemic (S) -Ibuprofen- (S)-(+)-1- from ibuprofen Aminoindan Salt manufacture

200 ml of methanol was added to the reactor, and 20.0 g of ibuprofen and 12.5 g (1 equivalent) of (S)-(+)-1-aminoindan were added dropwise as a reaction, followed by heating to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. The recrystallization was repeated four times to obtain (S) -Ibuprofen- (S)-(+)-1-aminoindane salt.

B-2. Preparation of (S) -Ibuprofen from (S) -Ibuprofen- (S)-(+)-1-aminoindone salt

(S) -Ibuprofen- (S)-(+)-1-aminoindane salt was added to the reactor, and 100 ml of 1N-HCl was added thereto, and the precipitated white (S) -ibuprofen was obtained by filtration.

The yield of ibuprofen was 4.65 g, the yield was 23.3%, and the optical activity was measured by the same method as in C. of Example 1, and the ratio of the (S) -isomer was 99.51%, (R) The proportion of isomers was 0.49%.

< Example 8: (S)-(+)-1- Amino indane using Racemic From ketoprofen (S) -ke Toffee Lofen manufacturing>

A. Preparation of (S) -ketoprofen- (S)-(+)-1-aminoindane salts from racemic ketoprofen

200 ml of methanol was added to the reactor, 20.0 g of ketoprofen and 10.4 g (1.0 equiv) of (S)-(+)-1-aminoindan were added dropwise as a reaction, followed by heating to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated 4 times to obtain (S) -ketoprofen- (S)-(+)-1-aminoindane salt.

B-2. Preparation of (S) -ketoprofen from (S) -ketoprofen- (S)-(+)-1-aminoindone salt

(S) -Ketoprofen- (S)-(+)-1-aminoindane salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white precipitated (S) -ketoprofen.

The yield of the (S) -ketoprofen was 5.37 g, the yield was 26.9%, and the optical activity was measured by the same method as in C. of Example 2, the ratio of the (S)-isomer is 99.55 % And the proportion of (R) -isomer was 0.45%.

< Example 9 :. (S)-(+)-1- Amino indane using Racemic From zaltoprofen (S) -well Toffee Lofen manufacturing>

A. Preparation of (S) -Zaltoprofen- (S)-(+)-1-aminoindane Salts from Racemic Zaltoprofen

200 ml of methanol was added to the reactor, and 20.0 g of zaltoprofen and 8.9 g (1.0 equiv) of (S)-(+)-1-aminoindan were added dropwise as a reaction, followed by heating to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated 4 times to obtain (S) -zaltoprofen- (S)-(+)-1-aminoindane salt.

B-2. (S) - Zaltoprofen -(S)-(+)-1- From aminoindan salts (S) - Of saltoprofen Produce

(S) -Zaltoprofen- (S)-(+)-1-aminoindane salt was added to the reactor, and 100 ml of 1N-HCl was added to the precipitated white (S) -Zaltoprofen.

The yield of (S) -zaltoprofen was 6.07 g, the yield was 30.4%, and the optical activity was measured by the same method as in C. of Example 3, and the ratio of (S) -isomer was 99.03. % And the ratio of (R) -isomer was 0.97%.

< Example 10: (S)-(+)-1- Amino indane using Racemic From flurbiprofen (S) - Flulubiprofen Manufacturing>

200 ml of methanol was added to the reactor, 20.0 g of flurbiprofen and 10.9 g (1.0 equiv) of (S)-(+)-1-aminoindan were added dropwise as a reactant, followed by heating to 80 ° C. to completely dissolve the reaction. . The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated 4 times to obtain (S) -flubipropene- (S)-(+)-1-aminoindane salt.

B-2. (S) - Flulubiprofen -(S)-(+)-1- From aminoindan salts (S) - Of flubiprofen Produce

(S) -Flubiprofen- (S)-(+)-1-aminoindone salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white precipitated (S) -Flubiprofen. .

The yield of the (S) -flubiprofen was 4.73 g, the yield was 23.7%, and the optical activity was measured by the same method as in C. of Example 4, the ratio of the (S) -isomer This was 99.23%, and the ratio of the (R) -isomer was 0.77%.

< Example 11: (S)-(+)-1- Amino indane using Racemic (S) -naproxen production from naproxen>

A. Racemic From naproxen (S) -naproxen- (S)-(+)-1- Aminoindan Salt manufacture

200 ml of methanol was added to the reactor, and 20.0 g of naproxen and 11.6 g (1.0 equiv) of (S)-(+)-1-aminoindan were added dropwise as a reactant, followed by heating to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated 4 times to obtain (S) -naproxen- (S)-(+)-1-aminoindane salt.

B-2. (S) -naproxen- (S)-(+)-1- From aminoindan salts Preparation of (S) -naproxen

(S) -naproxen- (S)-(+)-1-aminoindane salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white precipitated (S) -naproxen.

The yield of the (S) -naproxen was 4.83 g, the yield was 24.2%, and the optical activity was measured in the same manner as in C. of Example 5, the ratio of the (S)-isomer was 99.15% , (R)-isomer ratio was 0.85%.

< Example 12: (S)-(+)-1- Amino indane using Racemic From phenopropene (S) -fe Nov Lofen manufacturing>

A. Preparation of (S) -phenopropene- (S)-(+)-1-aminoindane Salts from Racemic Phenopropene

200 ml of methanol was added to the reactor, 20.0 g of phenopropene and 11.0 g (1.0 equiv) of (S)-(+)-1-aminoindan were added dropwise as a reactant, followed by heating to 80 ° C. to completely dissolve the reaction. The reaction solution was cooled to 25 ° C., left to stand for 1 hour and immediately filtered after recrystallization. The precipitate and filtrate were separated separately, the precipitate was dried and the filtrate was distilled under reduced pressure. Recrystallization was repeated 4 times to obtain (S) -phenopropene- (S)-(+)-1-aminoindane salt.

B-2. (S) - Phenopropene -(S)-(+)-1- From aminoindan salts (S) - Phenopropene Produce

(S) -phenopropene- (S)-(+)-1-aminoindane salt was added to the reactor, and 100 ml of 1N-HCl was added thereto to obtain white precipitated (S) -phenopropene.

The yield of (S) -phenopropene was 4.80 g, the yield was 24.2%, and the optical activity was measured by the same method as in C. of Example 6, whereby the ratio of (S) -isomer was 99.12% and the ratio of (R) -isomer was 0.88%.

Claims

2-Syl propionic acid containing an excess of racemic or S isomer and (S)-(+)-1-aminoindan by dissolving agent in a polar solvent, followed by heating reaction and cooling to (S) -2-aryl Preparing propionic acid- (S)-(+)-1-aminoindane salt as a crystal (step 1); And
To the isolated (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt, an aqueous inorganic acid solution and an organic solvent were added to extract (S) -2-arylpropionic acid as an organic solvent layer, and then an organic solvent. Concentrating the layer under reduced pressure to produce (S) -2-arylpropionic acid (step 2-1); includes;
The 2-arylpropionic acid has high yield and high purity optical activity, characterized in that any one selected from the group consisting of ibuprofen, naproxen, ketoprofen, zaltoprofen, flurbiprofen, and phenofene (S) -2-Arylpropionic acid production method.

2-Syl propionic acid containing an excess of racemic or S isomer and (S)-(+)-1-aminoindan by dissolving agent in a polar solvent, followed by heating reaction and cooling to (S) -2-aryl Preparing propionic acid- (S)-(+)-1-aminoindane salt as a crystal (step 1); And
Preparing an aqueous solution of (S) -2-arylpropionic acid by adding an aqueous inorganic acid solution to the isolated (S) -2-arylpropionic acid- (S)-(+)-1-aminoindane salt to produce (S) -2-arylpropionic acid (2). -2 process);
The 2-arylpropionic acid has high yield and high purity optical activity, characterized in that any one selected from the group consisting of ibuprofen, naproxen, ketoprofen, zaltoprofen, flurbiprofen, and phenofene (S) -2-Arylpropionic acid production method.

The method of claim 1,
The inorganic base aqueous solution and the organic solvent were added to the inorganic acid aqueous solution layer of step 2-1, and (S)-(+)-1-aminoindan was extracted with the organic solvent layer and concentrated under reduced pressure to give (S)-(+)-1- Obtaining amino indan (3 steps);
Method for producing (S) -2-arylpropionic acid having high yield and high purity optical activity, characterized in that it further comprises.

The method of claim 2,
An inorganic base aqueous solution and an organic solvent were added to the inorganic acid aqueous solution layer of step 2-2, and (S)-(+)-1-aminoindan was extracted with an organic solvent layer and concentrated under reduced pressure to give (S)-(+)-1- Obtaining amino indan (3 steps);
Method for producing (S) -2-arylpropionic acid having high yield and high purity optical activity, characterized in that it further comprises.

delete

The method according to any one of claims 1 to 4,
(S) -2-arylpropionic acid having high yield and high purity optical activity, characterized in that the amount of the (S)-(+)-1-aminoindane is 0.5 to 1.0 equivalent to the 2-arylpropionic acid. Manufacturing method.

The method according to any one of claims 1 to 4,
The polar solvent is a solvent selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, lower alcohols having 1 to 4 carbon atoms and water, and acetonitrile (S) Method for preparing 2-arylpropionic acid.

The method according to any one of claims 1 to 4,
The inorganic acid aqueous solution is a method of producing (S) -2-arylpropionic acid having high yield and high purity optical activity, characterized in that the aqueous solution of hydrochloric acid.

The method according to any one of claims 1, 3 and 4,
The organic solvent is dichloromethane, characterized in that the production method of (S) -2-arylpropionic acid having high yield and high purity optical activity.

The method according to claim 3 or 4,
The inorganic base is a method for producing (S) -2-arylpropionic acid having high yield and high purity optical activity, characterized in that selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.