KR101198676B1 - Method for preparing optically active 2-arylpropionic acid drugs using S-+-1,2,3,4-tetrahydro-1- naphthylamine - Google Patents

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 containing an excess of racemic or S isomers and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine are dissolved in a polar solvent and then heated and reacted. Cooling to prepare (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt as crystals (step 1); And (S)-by adding an aqueous inorganic acid solution and an organic solvent to the separated (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt. Extracting 2-arylpropionic acid into an organic solvent layer and then concentrating the organic solvent layer under reduced pressure to produce (S) -2-arylpropionic acid (Step 2-1) or the separated (S) -2-arylpropionic acid-( S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the aqueous solution of inorganic acid to precipitate the resulting precipitate to produce (S) -2-arylpropionic acid (2- 2 step); characterized in that it comprises a.
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-based drugs using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine using (S)-(+)-1,2,3,4-tetrahydro-1- naphthylamine}

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 inhibitory effect, it is widely used for the treatment of pain and infection, especially headache, neuralgia, etc. in musculoskeletal diseases such as rheumatic diseases.

[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. It is necessary to perform recrystallization more than once 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 splitting agent, but in order to obtain high purity (S) -ibuprofen, the chiral of ibuprofen The disadvantage is that the methylbenzylamine 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 of separating (S) -ketoprofen having optical activity from racemic ketoprofen, wherein cinchonidine is reacted on an organic solvent as a splitting agent. The method does not disclose a method for recovering used cicononidine.

In addition, Korean Patent Publication No. 2003-2955 discloses (S) -Ibuprofen-N by using N-octyl-D-glucamine as a dividing agent in an amount of 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.

Another object of the present invention is that the manufacturing process is simple, and the (S) -isomer 2-arylpropionic acid-based drug is separated from the racemic 2-arylpropionic acid-based drug, and then the resolving agent used is By easily recovering and reusing, it is to provide a method for preparing a 2-arylpropionic acid-based drug having improved optical activity.

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) 2-arylpropionic acid containing excess racemic or S isomers and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine ((S)-( +)-1,2,3,4-tetrahydro-1-naphthylamine) was dissolved in a polar solvent, heated and then cooled to give (S) -2-arylpropionic acid- (S)-(+)-1, Preparing a 2,3,4-tetrahydro-1-naphthylamine salt as a crystal (step 1); And

(b-1) To the isolated (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, an aqueous inorganic acid solution and an organic solvent were added to Extracting (S) -2-arylpropionic acid into an organic solvent layer and then concentrating 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is dissolved in a polar solvent with 2-arylpropionic acid containing an excess of racemic or S isomer and a splitting agent. Thereafter, the mixture was heated and then cooled to prepare (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt as crystals (1). fair); And

(b-2) To the isolated (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, an aqueous solution of inorganic acid is added and acidic (pH 5 or less), followed by filtration to produce (S) -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) (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine by 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. Extraction with an organic solvent layer and concentration under reduced pressure to obtain (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine (step 3).

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 ( S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine (S)-further comprising the step of obtaining (S)-with high yield and high purity optical activity Provided is a method for preparing 2-arylpropionic acid.

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

Step (a): Racemic  2- Arylpropionic acid  (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  By reaction (S) -2- Arylpropionic acid -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  Salt manufacture

As a first step of the present invention, a polar solvent is formed of 2-arylpropionic acid and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine containing an excess of racemic or S isomers. After dissolving in, followed by heating and cooling to prepare (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine used as the dividing agent is a chiral methylbenzylamine, N- Unlike octyl-D-glucamine salts, (S) -lysine, or cinchonidine, its conformation is fixed, forming a very stable salt with 2-arylpropionic acids to easily form crystals. There is an advantage. Accordingly, the present invention is directed to separating (S) -isomers of 2-arylpropionic acid class drugs using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine as the dividing agent. In addition, the 2-arylpropionic acid-based pharmacologically useful drug can be manufactured in high yield and high purity at a lower cost than the conventional manufacturing method, thereby improving economic efficiency of the entire 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is controlled by molar ratio. It is preferable. According to a preferred embodiment of the invention, the molar ratio of the 2-arylpropionic acid based drug to (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine are added to the polar solvent to react, thereby having a structure of (S) -isomer. Allow (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt of the arylpropionic acid-based drug to be produced, and then heat and cool to recrystallize (S) -2-aryl. The propionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt is separated.

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

As step (b-1) of the present invention, (S)-(+)-1,2,3,4-tetrahydro-1 of (S) -isomer 2-arylpropionic acid separated in step (a) After adding an inorganic acid aqueous solution and an organic solvent to the naphthylamine salt, extracting the (S) -isomer 2-arylpropionic acid-based drug into the organic solvent layer, and then concentrating the organic solvent layer under reduced pressure to obtain the (S) -isomer. 2-arylpropionic acid-based drugs are obtained.

Alternatively, according to another embodiment of the present invention, as (b-2), (S)-(+)-1,2 of the (S) -isomer 2-arylpropionic acid-based drug separated in the step (a) An aqueous inorganic acid solution is added to the, 3,4-tetrahydro-1-naphthylamine 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)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  collection

To the inorganic acid aqueous solution layer of step (b-1) or (b-2), an inorganic base is added to basify to pH 11 or more, and an organic solvent is added to (S)-(+)-1,2, 3,4-tetrahydro-1-naphthylamine is extracted with an organic solvent layer and then concentrated under reduced pressure.

As the inorganic base, an inorganic base 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)-(+)-1,2,3,4- from the filtrate obtained in step (a) Tetrahydro -One- Naphthylamine  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)-( The method may further include recovering +)-1,2,3,4-tetrahydro-1-naphthylamine. 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)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  (S) -Ibuprofen Preparation from Ibuprofen>

A. Racemic  (S) -Ibuprofen- (S)-(+)-1,2,3,4- from Ibuprofen Tetrahydro -One- I Propylamine salt preparation

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, 20.0 g of ibuprofen and (S)-(+)-1,2,3,4-tetrahydro as reactants -1-naphthylamine (7.3 g (0.5 equiv), or 10.2 g (0.7 equiv), or 14.6 g (1.0 equiv)) was added drop wise 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) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small amount of samples were taken and analyzed by HPLC. Make sure that you have satisfactory purity. If satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-1. (S) -Ibuprofen- (S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  Preparation of (S) -Ibuprofen

In the reactor, (S) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was dissolved in 100 ml of 1N-HCl and 100 ml of dichloromethane, and the extracted organic layer was diluted with 100 ml of distilled water. After washing three times with, the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a 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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine 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

Of (S) -Ibuprofen prepared according to the reaction solvent in preparing (S) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic ibuprofen Yield and optical activity ratio results are shown in [Table 1].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol  0.5  5.28  26.4  99.22  0.78  0.7  5.31  26.6  99.36  0.64  1.0  5.57  27.9  99.02  0.98
80% methanol  0.5  4.56  22.8  99.11  0.89  0.7  4.32  21.6  98.87  1.13  1.0  5.21  26.1  99.22  0.78
ethanol  0.5  5.80  29.0  99.34  0.66  0.7  5.85  29.3  99.72  0.28  1.0  5.76  28.8  99.62  0.38
70% ethanol  0.5  6.02  30.6  99.56  0.44  0.7  5.91  29.6  99.82  0.18  1.0  6.32  31.6  99.76  0.24
Isopropanol  0.5  5.76  28.8  99.12  0.88  0.7  5.88  29.4  98.78  1.22  1.0  5.82  29.1  99.54  0.46
Acetonitrile  0.5  5.27  26.4  98.78  1.22  0.7  5.25  26.3  99.72  0.28  1.0  5.48  27.4  99.53  0.47

D. Ibuprofen from filtrate and Divider  collection

The filtrate obtained in step A was concentrated to give ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt with excessive (R) -isomer and 100 ml of 1N-HCl. After dissolving with 100ml of dichloromethane, the extracted organic layer was washed three times with 100ml of distilled water, and then the organic layer was dehydrated with anhydrous 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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine was obtained. The yield of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine obtained in step B-1 and recovered in this step was 99% or more.

< Example  2: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  From ketoprofen (S)- Ketoprofen  Manufacturing>

A. Preparation of (S) -ketoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salts from racemic ketoprofen

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20.0 g of ketoprofen as a reactant and (S)-(+)-1,2,3,4- Tetrahydro-1-naphthylamine (5.8 g (0.5 equiv), or 8.1 g (0.7 equiv), or 11.5 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 was repeated three times to obtain (S) -ketopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small amount of samples were taken by HPLC. Analyze and confirm that the purity is satisfactory. If satisfactory purity is not reached, recrystallization is performed once more to obtain high purity (S) -ketoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt. Got it.

B-1. (S) - Ketoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) - Ketoprofen  Produce

In the reactor, (S) -ketopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was dissolved in 100 ml of 1N-HCl and 100 ml of dichloromethane, and then the organic layer was extracted. After washing three times with 100ml of distilled water, the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a white (S) -ketoprofen.

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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine was obtained.

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

(S) -Ketopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic ketoprofen according to the reaction solvent, prepared (S The yield and optical activity ratio of) -ketoprofen are shown in [Table 2].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol  0.5  4.16  21.4  99.32  0.68  0.7  4.07  24.4  98.99  1.01  1.0  4.51  22.6  99.75  0.25
80% methanol  0.5  4.39  22.0  99.11  0.89  0.7  4.72  23.6  99.87  0.13  1.0  5.01  25.1  99.19  0.81
ethanol  0.5  4.89  24.5  99.43  0.57  0.7  5.31  26.6  99.59  0.41  1.0  5.38  26.9  99.63  0.37
70% ethanol  0.5  4.07  20.4  99.65  0.35  0.7  4.61  23.1  99.83  0.17  1.0  4.74  23.7  99.26  0.74
Isopropanol  0.5  4,87  24.4  98.62  1.38  0.7  5.55  27.8  99.82  0.18  1.0  5.63  28.2  99.05  0.95
Acetonitrile  0.5  4.79  24.0  99.27  0.73  0.7  5.06  25.3  99.45  0.55  1.0  4.92  24.6  98.54  1.46

< Example  3: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  From zaltoprofen (S)- Zaltoprofen  Manufacturing>

A. Racemic From zaltoprofen  (S) - Zaltoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  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 zaltoprofen and (S)-(+)-1,2,3,4- as reactants were added. Tetrahydro-1-naphthylamine (5.0 g (0.5 equiv), or 6.9 g (0.7 equiv), or 9.9 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. Recrystallization was repeated three times to obtain (S) -saltoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small amount of samples were taken by HPLC. Analyze and confirm that the purity is satisfactory. If satisfactory purity is not achieved, recrystallization is performed once more to obtain high purity (S) -saltoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt. Got it.

B-1. (S) - Zaltoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  Preparation of (S) -Zaltoprofen

The organic layer extracted after dissolving (S) -saltopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt in 100 ml of 1N-HCl and 100 ml of dichloromethane After washing three times with 100ml of distilled water, the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a white (S) -saltopropene.

NaOH was added dropwise to the water layer of the reaction to make a basic solution (pH 11 or more), and then dissolved with 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 (S). -(+)-1,2,3,4-tetrahydro-1-naphthylamine was obtained.

C. Purity Analysis

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

(S) -Zaltoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic zaltoprofen prepared according to the reaction solvent, The yield and optical activity ratio of) -zaltoprofen are shown in [Table 3].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol  0.5  5.39  27.0  98.77  1.23  0.7  5.84  29.2  99.43  0.57  1.0  5.91  29.6  99.21  0.79
80% methanol  0.5  4.06  20.3  98.84  1.16  0.7  4.08  20.4  99.72  0.28  1.0  4.25  21.3  99.63  0.37
ethanol  0.5  5.43  27.2  99.42  0.58  0.7  5.66  28.3  99.08  0.92  1.0  5.79  29.0  99.74  0.26
70% ethanol  0.5  5.00  25.0  99.77  0.23  0.7  5.31  26.6  99.67  0.33  1.0  5.42  27.1  99.51  0.49
Isopropanol  0.5  4.33  21.7  98.98  1.02  0.7  5.02  25.1  99.59  0.41  1.0  4.94  24.7  98.54  1.46
Acetonitrile  0.5  4.18  20.9  99.41  0.59  0.7  4.32  21.6  98.95  1.05  1.0  5.06  25.3  98.38  1.62

< Example  4: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  (S)-from flurbiprofen Flulubiprofen  Manufacturing>

A. Preparation of (S) -Flurbiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salts from racemic flurbiprofen

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)-(+)-1,2,3, 4-tetrahydro-1-naphthylamine (6.1 g (0.5 equiv), or 8.5 g (0.7 equiv), or 12.1 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. Recrystallization was repeated three times to obtain (S) -Flubiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small amount of samples were taken. Analyze by HPLC to ensure that the purity is satisfactory. If satisfactory purity is not achieved, recrystallization is performed once more to obtain high purity (S) -Flurbiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine A salt was obtained.

B-1. Preparation of (S) -Flubiprofen from (S) -Flubiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt

In the reactor, (S) -Flubiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was dissolved in 100 ml of 1N-HCl and 100 ml of dichloromethane, and extracted. The organic layer was washed three times with 100 ml of distilled water, and then the organic layer was dehydrated with anhydrous manganese and concentrated under reduced pressure to obtain a white (S) -flubipropene.

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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine was obtained.

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

According to the reaction solvent in the preparation of (S) -flurbiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic flubiprofen, The yield and optical activity ratio results of the prepared (S) -flubiprofen are shown in [Table 4].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol  0.5  5.38  26.9  98.96  1.04  0.7  5.82  29.1  99.49  0.51  1.0  6.27  31.4  99.53  0.47
80% methanol  0.5  5.21  26.1  98.94  1.06  0.7  4.98  24.9  99.55  0.45  1.0  5.26  26.3  99.48  0.52
ethanol  0.5  5.06  25.3  99.43  0.57  0.7  5.43  27.2  99.52  0.48  1.0  5.74  28.7  99.67  0.33
70% ethanol  0.5  5.77  28.9  98.76  1.24  0.7  5.32  26.6  99.62  0.38  1.0  6.11  30.6  99.75  0.25
Isopropanol  0.5  5.63  28.2  99.43  0.57  0.7  5.54  27.7  99.68  0.32  1.0  5.96  29.8  99.73  0.27
Acetonitrile  0.5  5.05  25.3  98.89  1.11  0.7  5.21  26.1  98.44  1.56  1.0  5.73  28.7  98.94  1.06

< Example  5: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  (S) -naproxen production from naproxen>

A. Racemic  From naproxen (S) -naproxen- (S)-(+)-1,2,3,4- Tetrahydro -1-Naphthylamine Salt Preparation

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)-(+)-1,2,3,4-tetrahydro as reactants -1-naphthylamine (6.4 g (0.5 equiv), or 9.0 g (0.7 equiv), or 12.8 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 was repeated three times to obtain (S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small sample was taken and analyzed by HPLC. Make sure that you have satisfactory purity. When satisfactory purity was not reached, recrystallization was performed once more to obtain a high purity (S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-1. Preparation of (S) -naproxen from (S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt

In the reactor, (S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was dissolved in 100 ml of 1N-HCl and 100 ml of dichloromethane, and the extracted organic layer was diluted with 100 ml of distilled water. After washing three times with, the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a white (S) -naproxen.

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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine 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 = 96/4 / 0.1 (ｖ / ｖ)

Flow rate: 1 ml / min

-Detector: Tunable Absorbance Detector, UV 210 nm

Injection volume: 5 μl

Of (S) -naproxen prepared according to the reaction solvent in preparing (S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic naproxen Yield and optical activity ratio results are shown in [Table 5].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol
 0.5  5.42  27.1  98.23  1.77  0.7  6.08  30.4  99.07  0.93  1.0  6.41  32.1  99.26  0.74
80% methanol  0.5  5.32  26.6  98.02  1.98  0.7  4.72  23.6  99.25  0.75  1.0  5.49  27.5  99.41  0.59
ethanol  0.5  5.06  25.3  98.97  1.03  0.7  5.34  26.7  99.45  0.55  1.0  5.72  28.6  99.68  0.32
70% ethanol  0.5  5.18  25.9  99.47  0.53  0.7  4.90  24.5  99.77  0.23  1.0  5.57  27.9  99.54  0.46
Isopropanol  0.5  4.56  22.8  99.15  0.85  0.7  5.38  26.9  99.84  0.16  1.0  5.84  29.2  99.67  0.33
Acetonitrile  0.5  4.64  23.2  97.55  2.45  0.7  4.88  24.4  98.65  1.35  1.0  4.05  20.3  98.89  1.11

< Example  6: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic From phenopropene  (S) -fe Nov Lofen manufacturing>

A. Racemic From phenopropene  (S) - Phenopropene -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  Salt manufacture

200 ml of solvent (methanol, 80% methanol, ethanol, 70% ethanol, isopropanol, or acetonitrile) was added to the reactor, and 20 g of phenopropene and (S)-(+)-1,2,3,4- as a reactant were added. Tetrahydro-1-naphthylamine (6.1 g (0.5 equiv), or 8.5 g (0.7 equiv), or 12.2 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 was repeated three times to obtain (S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and a small amount of samples were taken to obtain HPLC. Analyze the test to see if it shows satisfactory purity. If satisfactory purity is not reached, recrystallization is performed once more to obtain high purity (S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt. Got it.

B-1. (S) - Phenopropene -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) -fe Nopro Manufacture of pen

Organic layer extracted after dissolving (S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt in 100 ml of 1N-HCl and 100 ml of dichloromethane Was washed three times with 100 ml of distilled water, and then the organic layer was dehydrated with anhydrous forget-me-not and concentrated under reduced pressure to obtain a white (S) -phenopropene.

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. -(+)-1,2,3,4-tetrahydro-1-naphthylamine was obtained.

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

Prepared according to the reaction solvent when preparing (S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt from racemic phenpropene The yield and the optical activity ratio of (S) -phenopropene are shown in [Table 6].

menstruum

Split amount equivalent
Yield (g)
yield(%)
S ratio (%)
R ratio (%)
Methanol  0.5  4.88  24.4  98.00  2.00  0.7  4.94  24.7  99.42  0.58  1.0  4.36  21.8  98.02  1.98
80% methanol  0.5  5.32  26.6  99.53  0.47  0.7  5.02  25.1  99.37  0.63  1.0  5.48  27.4  98.64  1.36
ethanol  0.5  4.73  23.7  98.08  1.92  0.7  5.33  26.7  99.22  0.78  1.0  5.29  26.5  98.72  1.28
70% ethanol  0.5  4.99  25.0  99.48  0.52  0.7  5.22  26.1  99.54  0.46  1.0  4.72  23.6  99.29  0.71
Isopropanol  0.5  5.02  25.1  99.73  0.27  0.7  5.15  25.8  99.46  0.54  1.0  5.87  29.4  98.95  1.05
Acetonitrile  0.5  5.38  26.9  98.12  1.88  0.7  5.56  27.8  98.29  1.71  1.0  6.45  32.3  98.70  1.30

< Example  7: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  (S) -Ibuprofen Preparation from Ibuprofen>

A. Preparation of (S) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salts from racemic ibuprofen

200 ml of methanol was added to the reactor, and 20.0 g of ibuprofen and 14.6 g (1.0 equiv) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise as a reactant, followed by 80 占 폚. Heated to complete dissolution of 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) -Ibuprofen- (S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  Preparation of (S) -Ibuprofen

(S) -Ibuprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white (S). Ibuprofen was obtained by filtration.

The yield of (S) -Ibuprofen was 5.15 g, the yield was 25.8%, and the optical activity was measured by the same method as in C. of Example 1, and the ratio of the (S) -isomer was 99.49%. , (R)-isomer ratio was 0.51%.

< Example  8: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  From ketoprofen (S)- Ketoprofen  Manufacturing>

A. Racemic From ketoprofen  (S) - Ketoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  Salt manufacture

200 ml of methanol was added to the reactor, and 20.0 g of ketoprofen and 11.5 g (1.0 equiv) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise as a reactant. Heating to 80 ° C. completely dissolved 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) -ketopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) - Ketoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) -ke Bupro Manufacture of pen

(S) -Ketopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate the white (S ) -Ketoprofen was obtained.

The yield of (S) -ketoprofen was 4.82 g, the yield was 24.1%, and the optical activity was measured by the same method as in C. of Example 2, and the ratio of (S) -isomer was 99.57. % And the ratio of (R) -isomer was 0.43%.

< Example  9: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  From zaltoprofen (S)- Zaltoprofen  Manufacturing>

A. Racemic From zaltoprofen  (S) - Zaltoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  Salt manufacture

200 ml of methanol was added to the reactor, 20.0 g of zaltoprofen and 9.9 g (1.0 equiv) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise, followed by 80 占 폚. Heated to complete dissolution of 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) -saltopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) - Zaltoprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) - Of saltoprofen  Produce

(S) -Zaltoprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate the white (S ) -Zaltoprofen was obtained by filtration.

The yield of the (S) -zaltoprofen was 5.70 g, the yield was 28.5%, and the optical activity was measured by the same method as in C. of Example 3, and the ratio of the (S) -isomer was 99.61. % And the ratio of (R) -isomer was 0.39%.

Example 10 Preparation of (S) -Flubiprofen from Racemic Flubiprofen Using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine >

A. Racemic From flurbiprofen  (S) - Flulubiprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthyl Salt salt manufacturing

200 ml of methanol was added to the reactor, and 20.0 g of flurbiprofen and 12.1 g (1 equivalent) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise as a reactant. The reaction was then completely dissolved by heating to 80 ° C. 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) -flubipropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) - Flulubiprofen -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) - Pluvipro Manufacture of pen

(S) -Flurbiprofen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white. (S) -Flubiprofen was obtained by filtration.

The yield of (S) -flubiprofen was 6.19 g, the yield was 30.95%, and the optical activity was measured by the same method as in C. of Example 4, whereby the ratio of (S) -isomer This was 99.57%, and the ratio of the (R) -isomer was 0.43%.

< Example  11: (S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  using Racemic  (S) -naproxen production from naproxen>

A. Racemic  From naproxen (S) -naproxen- (S)-(+)-1,2,3,4- Tetrahydro -1-Naphthylamine Salt Preparation

200 ml of methanol was added to the reactor, and 20.0 g of naproxen and 12.8 g (1.0 equiv) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise as a reactant, followed by 80 占 폚. Heated to complete dissolution of 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)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) -naproxen- (S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  Preparation of (S) -naproxen

(S) -naproxen- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate white (S)-. Naproxen was obtained by filtration.

The yield of the (S) -naproxen was 6.28 g, the yield was 31.4%, and the optical activity was measured by the same method as in C. of Example 5, the ratio of the (S)-isomer was 99.32% , (R)-isomer ratio was 0.68%.

Example 12 Preparation of (S) -phenopropene from racemic phenopropene using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine

A. Racemic From phenopropene  (S) - Phenopropene -(S)-(+)-1,2,3,4- Tetrahydro -One- Naphthylamine  Salt manufacture

200 ml of methanol was added to the reactor, and 20 g of phenopropene and 12.2 g (1.0 equiv) of (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine were added dropwise as a reactant. Heating to 80 ° C. completely dissolved 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 a (S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt.

B-2. (S) - Phenopropene -(S)-(+)-1,2,3,4- Tetrahydro -One- From naphthylamine salt  (S) - Phenopropene  Produce

(S) -phenopropene- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt was added to the reactor, and 100 ml of 1N-HCl was added to precipitate the white ( S) -phenopropene was obtained by filtration.

The yield of (S) -phenopropene was 4.29 g, the yield was 21.5%, and the optical activity was measured by the same method as in C. of Example 6, whereby the ratio of (S) -isomer was 99.07% and the ratio of (R) -isomers was 0.93%.

Claims (10)

2-Sylpropionic acid containing an excess of racemic or S isomer and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine with a splitting agent were dissolved in a polar solvent and then heated. Reacting and cooling to prepare (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt as crystals (step 1); And
To the isolated (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, an aqueous inorganic acid solution and an organic solvent were added to (S) -2 Extracting arylpropionic acid into an organic solvent layer and then concentrating the organic solvent layer under reduced pressure to produce (S) -2-arylpropionic acid (step 2-1); and
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-Sylpropionic acid containing an excess of racemic or S isomer and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine with a splitting agent were dissolved in a polar solvent and then heated. Reacting and cooling to prepare (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt as crystals (step 1); And
An aqueous inorganic acid solution was added to the isolated (S) -2-arylpropionic acid- (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine salt, and the precipitate produced was filtered. It comprises a)-2-arylpropionic acid (step 2-2);
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 to extract (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine into the organic solvent layer and depressurize it. Concentration to obtain (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine (step 3);
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 to extract (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine into the organic solvent layer and reduced pressure. Concentration to obtain (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine (step 3);
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,
The use amount of the (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is 0.5 to 1.0 equivalents based on the 2-arylpropionic acid, which is characterized by high yield and high purity. Method for preparing (S) -2-arylpropionic acid having optical activity. 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 for 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.