KR100503443B1 - Processes for preparing an optically active cetirizine or its salt - Google Patents

Abstract

The invention provides optically from racemic forms of cetirizine or salts thereof using glutamate of 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid ester The above 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl useful as a process for preparing active cetirizine or salts thereof and as an intermediate for preparing optically active cetirizine or salts thereof. Glutamate of] ethoxy] acetic acid ester.

Description

Processes for preparing an optically active cetirizine or its salt

The present invention relates to a process for the optical resolution of cetirizine or salts thereof in racemic form, more particularly 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl ] Methods for preparing optically active cetirizine or salts thereof from racemic forms of cetirizine or salts thereof using glutamate of] ethoxy] acetic acid ester and the above useful as an intermediate for preparing optically active cetirizine or salts thereof. And glutamate of-[2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid ester.

Cetirizine is a substance known as an antihistamine represented by the following structural formula, and is usually used in the form of a dihydrochloride salt. The chemical formula is 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1- Piperazinyl] ethoxy] acetic acid.

In addition, optical actives of cetirizine, including levo- or dextro-cetirizine dihydrochloride, are known for a variety of additional pharmacological effects. For example, US Pat. No. 5,627,183 discloses that (+)-cetirizine is effective for urticaria, while US Pat. No. 5,698,558 describes (-)-cetirizine for allergic rhinitis. Has been shown to be effective.

Meanwhile, British Patent No. 2,225,321 (Korean Patent Publication No. 1990-7825) discloses a method for preparing an optical isomer of cetirizine. That is, a method for preparing optically active cetirizine or a salt thereof from optically active acetonitrile-intermediates is disclosed. U.S. Pat.No. 5,478,941 (Korean Patent Publication No. 194-21541, EP 955,295) also discloses an optically active cetirizine or salt thereof using (4-methylphenyl) sulfonyl-piperazine derivatives as intermediates. Disclosed is a method of manufacturing.

However, the conventional method is a method for preparing the final material cetirizine or a salt thereof by using an optically active intermediate, which requires a multi-step manufacturing process, the yield is not satisfactory. That is, in the case of British Patent No. 2,225,321, the optical resolution of the starting material 1-[(4-chlorophenyl) phenylmethyl] piperazine is about 12.7%, and in the case of US Patent No. 5,478,941, the optical separation ( Preferential 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid via esters from-)-(4-chlorophenyl) phenylmethylamine as intermediate The yield of dihydrochloride is only about 29.3%.

The inventors of the present invention have continued to develop an improved method for preparing optically pure cetirizine or salts thereof. As a result, when the racemic form of cetirizine or salts thereof is converted into a glutamate-type intermediate, optical separation with high yield and purity is achieved. It was found that it was possible to complete the present invention.

Accordingly, an object of the present invention is to provide a method for preparing optically active cetirizine or a salt thereof.

It is also an object of the present invention to provide compounds useful as intermediates for the preparation of the cetirizine or salts thereof.

According to one aspect of the invention, (a) reacting an optically active compound of formula (1) with a base to prepare an optically active compound of formula (2a); And (b) hydrolyzing the compound of Formula 2a, there is provided a process for preparing optically active cetirizine or a salt thereof:

In the formula, R ¹ is a C ₁ ~C ₆ alkyl, R ² is an amino protecting group.

The amino protective group includes a conventional amino protecting group, such as C ₁ ~C ₄ alkyl substituted by a lower or unsubstituted phenylsulfonyl, a sulfonyl, acetyl substituted by a lower alkyl of C ₁ ~C _4, Ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, benzoyl, nicotinoyl, phthaloyl and the like. Preferably the amino protecting group may be phenylsulfonyl, (4-methylphenyl) sulfonyl.

In the preparation method of the present invention, as the base usable in step (a), conventional organic or inorganic bases may be used, for example, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide And the like. In addition, the reaction of step (a) may be carried out in a nonpolar organic solvent and a mixed solvent of water, preferably a mixed solvent of methylene chloride and water, or a mixed solvent of ethyl acetate and water, and the nonpolar organic solvent The mixing ratio with water is preferably about 1: 1 (V / V). The resulting optically active compound of formula (2a) can be separated by conventional methods. For example, the organic layer can be extracted, washed if necessary, dried and concentrated to separate.

On the other hand, glutamic acid having the amino protecting group can be recovered and reused. That is, glutamic acid having an amino protecting group generated in step (a) is transferred to the aqueous layer, pH is adjusted to 3 or less by adding hydrochloric acid to the aqueous layer, extracted with an organic solvent such as ethyl acetate, and the organic layers are combined in a conventional manner. After drying, it is filtered and washed. The organic phase can be concentrated, crystallized in an organic solvent such as diisopropyl ether and filtered to recover and reuse in a yield of about 82%. In particular, considering that D-glutamic acid is about 25 times more expensive reagent than L-glutamic acid, the production method of the present invention that can recover and reuse it is economically very advantageous.

The hydrolysis reaction of step (b) can be carried out under acidic or basic conditions, preferably under basic conditions. When the hydrolysis reaction is carried out under basic conditions, it can be carried out using 1 to 2 equivalents of sodium hydroxide or potassium hydroxide. In addition, the hydrolysis reaction may be performed in an alcohol such as methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, and preferably, in a mixed solvent of methanol and water. When using the mixed solvent, the mixing ratio of alcohol and water may be about 4: 6 (V / V). In addition, the hydrolysis reaction can be carried out at 0 ℃ to reflux temperature, preferably at 20 to 40 ℃. If necessary, the reaction solution can be purified by washing with ethyl acetate, etc., by adding hydrochloric acid to the washed aqueous solution to maintain a pH of 4 to 5, extracted with methylene chloride and the like and combined the organic layer. The obtained organic layer can be dried by a conventional method.

In the preparation method of the present invention, hydrolysis products obtained by performing step (b) may be prepared by hydrochloric acid of cetirizine which is optically active by reacting hydrochloric acid in an organic solvent such as acetone.

The optically active compound of formula (I), which is used as a starting material of the preparation method of the present invention, may be prepared by reacting a compound of formula (2b) and an optically active compound of formula (3) in a racemic body:

In the formula, R ¹ and R ² are as defined above.

The compound of Formula 2b may be prepared by the preparation method disclosed in European Patent Publication No. 58,146, or may be easily prepared by acid-catalyzed esterification of cetirizine dihydrochloride in alcohol.

In addition, the compound of Formula 3 may be purchased commercially, or may be prepared by reacting glutamic acid with a conventional amino protecting group. The amino protecting group is a C ₁ ~C ₄ lower alkyl substituted by or unsubstituted phenylsulfonyl, substituted by lower alkyl of C ₁ ~C _4-sulfonyl, acetyl, ethoxy-carbonyl, t- butoxycarbonyl , Benzyloxycarbonyl, benzoyl, nicotinoyl, phthaloyl and the like can be used, and preferably phenylsulfonyl, (4-methylphenyl) sulfonyl and the like can be used. For example, when phenylsulfonyl or (4-methylphenyl) sulfonyl is used as the amino protecting group, glutamic acid and phenylsulfonyl chloride or (4-methylphenyl) sulfonyl chloride are used in the presence of a base such as triethylamine in a conventional organic solvent. It can be prepared by reacting a mixed solvent of water with water, for example, a mixed solvent of tetrahydrofuran and water.

The reaction of the compound of Formula 2b and the optically active compound of Formula 3 may be carried out in an alcohol selected from the group consisting of methanol, ethanol, and isopropanol or a mixed solvent of alcohol and water, more preferably ethanol, It can be carried out in isopropanol or isopropanol-water (95: 5 V / V) mixed solvent. The compound of Formula 3 may be carried out using 0.4 to 2.2 mole, preferably 0.4 to 1.1 mole with respect to 1 mole of the compound of Formula 2b. In addition, the reaction can be carried out at 0 ℃ to reflux temperature, preferably about 60 to 82 ℃ (or reflux temperature of the solvent).

After performing a reaction with the compound of Formula 2b and the optically active compound of Formula 3 as described above, the optically active compound of Formula 1 obtained is an alcohol or the alcohol selected from the group consisting of methanol, ethanol, and isopropanol Higher purity products can be obtained by recrystallization in a mixed solvent of water and water. The recrystallization is refluxed and then slowly cooled to produce a product of higher purity by filtering the resulting solid at 20 ~ 40 ℃, preferably at room temperature.

The compound of Formula 1 obtained above is obtained as an optically active compound, and thus, it can be used to prepare an optically active cetirizine or a salt thereof. That is, the optically pure compound of Formula 1 may be separated by performing a conventional filtration process.

For example, when the solid obtained through the filtration process is used in the next reaction, reacting the compound of Formula 2b with the compound of Formula 3 of L-form gives a compound of Formula 1 of priority, which is reacted with a base. After hydrolysis and hydrolysis, hydrocyanic cetirizine dihydrochloride is obtained. In addition, when the compound of Formula 2b reacts with the compound of Formula 3 in the D-form, the compound of formula 1 is obtained, and reacted with a base and hydrolyzed with hydrochloric acid to give preferential cetirizine dihydrochloride. Will be obtained.

When the filtrate obtained through the filtration process is used for the next reaction, when the compound of Formula 2b reacts with the compound of Formula 3 of D-form, the compound of Formula 1 is obtained in the filtrate, and reacted with a base. When hydrolyzed and reacted with hydrochloric acid, sedentary cetirizine dihydrochloride is obtained. In addition, when the compound of formula 2b reacts with the compound of formula 3 in L-form, the compound of formula 1 is obtained in a filtrate {[α] ²⁵ ₃₆₅ : +84.50 (c = 1, methanol)}, and the base and When reacted, hydrolyzed and reacted with hydrochloric acid, preferential cetirizine dihydrochloride {[α] ²⁵ ₃₆₅ : + 10.91 (c = 1, water): optical purity 87% ee} is obtained.

On the other hand, considering that D-glutamic acid is about 25 times higher than L-glutamic acid (based on Aldrich's price), in the case of preparing lecithin cetirizine dihydrochloride, the compound of Formula 2b and L-form of Formula 3 It is preferable to use the compound of the formula (1) obtained after the reaction of the compound of the present invention in the solid phase by filtration, and to prepare the preferential cetirizine dihydrochloride, the compound of the formula (2b) and the L-form of formula (3) It is preferable to use the compound of the formula (1) obtained by reacting the compound of the reaction product, which is obtained by filtration with a filtrate.

According to another aspect of the present invention there is provided an optically active compound of formula 1, useful as an intermediate for the preparation of optically active cetirizine or its hydrochloride salt:

<Formula 1>

In the formula, R ¹ and R ² are as defined above.

Although the specific form of the compound of Formula 1 is not yet confirmed, it is assumed that Compound 1 mole of Formula 2a and Compound 1 mole of Formula 3 are combined in the form of a salt.

If the production method of the present invention is represented by the overall scheme, it is shown in Scheme 1.

In Scheme 1, R ¹ and R ² are as defined above.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are only for illustrating the present invention, and do not limit the present invention.

In the examples below, the optical purity is determined by high performance liquid chromatography (CHIRALCELL OD-R column, 250 × 4.6 mm; water (0.5 M NaClO ₄ , pH 2 buffer) -acetonitrile 60:40 (V / V) in chiral stationary phases. Mixed solvent: flow rate 0.5 ml / min). In addition, the fluorescence was measured by JASCO P-1030, nuclear magnetic resonance spectrum (NMR) was measured using a 300 MHz FT-NMR Spectrometer (JEOL JNM-LA300). Melting point was measured using Buchi B-545.

Example 1 Preparation of Racemic Methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate

100 g (0.217 mole) of cetirizine dihydrochloride of racemic body was dissolved in 400 ml methanol, and then 2 ml of concentrated sulfuric acid was added slowly. The reaction mixture was refluxed for 10 hours and then concentrated. 300 ml of methylene chloride was added to the residue obtained by concentration, neutralized with 300 ml of saturated aqueous sodium hydrogen carbonate solution, and the organic phase was extracted. 300 ml of methylene chloride was added to the aqueous phase, and extracted once more, and the organic phases were combined and washed twice with 200 ml of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, washed with methylene chloride and the organic phase was concentrated. 82.88 g of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate was obtained in the form of an oil.

Yield: 95.0%

¹ H-NMR (CDCl ₃ ) ppm: 2.43 (br s, 4H), 2.55 (br s, 4H), 2.64 (t, 2H), 3.66 (t, 2H), 3.72 (s, 3H), 4.10 (s , 2H), 4.20 (s, 1H), 7.15-7.30 (m, 5H), 7.33-7.37 (m, 4H)

Example 2. Preparation of (+)-N- (phenylsulfonyl) -D-glutamic acid

150 ml of water was added to 14.71 g (0.1 mole) of D-glutamic acid, and 42 ml (0.3 mole) of triethylamine were added slowly with stirring. 150 ml of tetrahydrofuran was added to the reaction mixture, which was then cooled to 5 ° C. 12.8 ml (0.1 mole) of benzenesulfonyl chloride was slowly added to the reaction mixture, followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was concentrated at 30 ° C. to remove tetrahydrofuran and washed with 150 ml of methylene chloride. 33.3 ml (0.2 mole) of 6 N aqueous hydrochloric acid was added to adjust the pH to 3 or less, and extracted three times in succession with 150 ml of ethyl acetate. The combined organic phases were washed with 100 ml of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate and the organic phase was concentrated. 150 ml of diisopropyl ether was added to the residue to crystallize. The resulting solid was filtered and washed with a small amount of diisopropyl ether to give 21.79 g of the desired (+)-N- (phenylsulfonyl) -D-glutamic acid.

m.p. : 133.1 ℃

Yield: 75.9%

¹ H-NMR (DMSO-d ₆ ) ppm: 1.59-1.69 (m, 1H), 1.80-1.86 (m, 1H), 2.17 (t, 2H), 3.76 (m, 1H), 7.51-7.63 (m, 3H), 7.73-7.76 (m, 2H), 8.15 (d, 1H), 12.40 (br s, 2H)

[α] ²⁴ ₅₈₉ : + 14.09 (c = 5, water)

Example 3. Preparation of (-)-N-[(4-methylphenyl) sulfonyl] -D-glutamic acid

(-)-N-[(4-methylphenyl) sulfonyl] -D-, except that 19.07 g (0.1 mole) of p-toluenesulfonyl chloride was used instead of benzenesulfonyl chloride. 23.53 g of glutamic acid were obtained.

m.p. : 127.3 ℃

Yield: 78.1%

¹ H-NMR (DMSO-d ₆ ) ppm: 1.58-1.68 (m, 1H), 1.76-1.88 (m, 1H), 2.18 (t, 2H), 2.35 (s, 3H), 3.73 (m, 1H) , 7.34 (d, 2H), 7.62 (d, 2H), 8.08 (d, 1H), 12.40 (br s, 2H)

[α] ²⁰ ₅₈₉ : -12.90 (c = 5, acetone)

Example 4 Preparation of Preferred Methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetateN- (phenylsulfonyl) -L-glutamate

12.75 g (0.032 mole) of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 was added to isopropanol-water (95 : 5 V / V) It was dissolved in 130 ml of a mixed solvent, heated to 60 ° C., and 9.3 g (0.032 mole) of (-)-N- (phenylsulfonyl) -L-glutamic acid was added thereto, followed by reaction for 1 hour. After cooling to room temperature, the precipitated solid was filtered, washed with a small amount of isopropanol-water mixed solvent, and dried. The dried solid was recrystallized in an isopropanol-water (95: 5 V / V) mixed solvent to give priority to methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 7.68 g of acetate N- (phenylsulfonyl) -L-glutamate were obtained.

m.p. : 124.3 ℃

Yield: 70.3%

¹ H-NMR (TFA-d ₁ ) ppm: 2.11-2.23 (m, 1H), 2.40-2.52 (m, 1H), 2.81 (t, 2H), 3.76 (br s, 2H), 3.93-4.17 (m , 11H), 4.32-4.41 (m, 5H), 5.54 (br s, 1H), 7.58-7.83 (m, 12H), 8.03 (d, 2H)

[α] ²⁵ ₃₆₅ : +94.90 (c = 1, methanol)

Example 5. Preparation of Lactose Methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N- (phenylsulfonyl) -D-glutamate

15.19 g (0.038 mole) of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 was added to isopropanol-water (95 : 5 V / V) was dissolved in 150 ml of a mixed solvent and heated to 60 ° C., and then 11.00 g (0.038 mole) of (+)-N- (phenylsulfonyl) -D-glutamic acid prepared in Example 2 was added thereto for 1 hour. Reacted for a while. After cooling to room temperature, the precipitated solid was filtered, washed with a small amount of isopropanol-water mixed solvent, and dried. The dried solid was recrystallized in an isopropanol-water (95: 5 V / V) mixed solvent to give a left linear methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 8.47 g of acetate N- (phenylsulfonyl) -D-glutamate were obtained.

m.p. : 125.4 ℃

Yield: 65.1%

¹ H-NMR (TFA-d ₁ ) ppm: 2.11-2.23 (m, 1H), 2.40-2.52 (m, 1H), 2.81 (t, 2H), 3.76 (br s, 2H), 3.93-4.17 (m , 11H), 4.36-4.41 (m, 5H), 5.54 (br s, 1H), 7.58-7.83 (m, 12H), 8.03 (d, 2H)

[α] ²⁵ ₃₆₅ :-92.23 (c = 1, methanol)

Example 6. Priority methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate.N-[(4-methylphenyl) sulfonyl] -L Preparation of Glutamate

13.07 g (0.032 mole) of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 was added to isopropanol-water (95 : 5 V / V) was dissolved in 130 ml of a mixed solvent and heated to 60 ° C., and then 10.00 g (0.033 mole) of (+)-N- (p-toluenesulfonyl) -L-glutamic acid was added and reacted for 1 hour. After cooling to room temperature, the precipitated solid was filtered, washed with a small amount of isopropanol-water mixed solvent, and dried. The dried solid was recrystallized in an isopropanol-water (95: 5 V / V) mixed solvent to give priority to methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 10.36 g of acetateN-[(4-methylphenyl) sulfonyl] -L-glutamate were obtained.

m.p. : 149.5 ℃

Yield: 90.7%

¹ H-NMR (TFA-d ₁ ) ppm: 2.23 (m, 1H), 2.49 (m, 1H), 2.61 (s, 3H), 2.85 (br s, 2H), 3.82 (br s, 2H), 4.03 -4.22 (m, 11H), 4.44 (m, 5H), 5.59 (br s, 1H), 7.57 (d, 2H), 7.66-7.73 (m, 9H), 7.96 (d, 2H)

[α] ²⁵ ₃₆₅ : + 110.73 (c = 1, methanol)

Example 7. Priority methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate.N-[(4-methylphenyl) sulfonyl] -L Preparation of Glutamate

10.00 g (0.025 mole) and (+)-N racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 7.85 g (0.026 mole) of-(p-toluenesulfonyl) -L-glutamic acid was carried out in the same manner as in Example 6 to obtain a solid. The obtained solid was recrystallized twice from ethanol to give more optically pure priority methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N- [ 5.58 g of (4-methylphenyl) sulfonyl] -L-glutamate was obtained.

m.p. : 150.2 ℃

Yield: 63.9%

¹ H-NMR (TFA-d ₁ ) ppm: 2.17-2.25 (m, 1H), 2.46-2.52 (m, 1H), 2.60 (s, 3H), 2.84 (t, 2H), 3.80 (br s, 2H ), 4.01-4.21 (m, 11H), 4.38-4.42 (m, 5H), 5.58 (br s, 1H), 7.55 (d, 2H), 7.62-7.73 (m, 9H), 7.94 (d, 2H)

[a] ²⁵ ₃₆₅ : + 111.00 (c = 1, methanol)

Example 8. Left-handed methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate.N-[(4-methylphenyl) sulfonyl] -D Preparation of Glutamate

13.74 g (0.034 mole) of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 was added to isopropanol-water (95 : 5 V / V) was dissolved in 140 ml of a mixed solvent and heated to 60 ° C., and then 10.50 g (0.035 mole) of (-)-N-[(4-methylphenyl) sulfonyl] -D-glutamic acid prepared in Example 3 was added. After the addition, the reaction was carried out for 1 hour. After cooling to room temperature, the precipitated solid was filtered, washed with a small amount of isopropanol-water mixed solvent, and dried. The dried solid was recrystallized in an isopropanol-water (95: 5 V / V) mixed solvent to give a left linear methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 10.10 g of acetateN-[(4-methylphenyl) sulfonyl] -D-glutamate were obtained.

m.p. : 150.2 ℃

Yield: 84.1%

¹ H-NMR (TFA-d ₁ ) ppm: 2.20 (m, 1H), 2.47 (m, 1H), 2.58 (s, 3H), 2.83 (t, 2H), 3.79 (br s, 2H), 4.00- 4.19 (m, 11H), 4.37-4.41 (m, 5H), 5.57 (br s, 1H), 7.54 (d, 2H), 7.61-7.72 (m, 9H), 7.93 (d, 2H)

[α] ²⁵ ₃₆₅ :-104.62 (c = 1, methanol)

Example 9. Left-handed methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate.N-[(4-methylphenyl) sulfonyl] -D Preparation of Glutamate

Prepared in Example 3 with 12.17 g (0.030 mole) of racemic methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate prepared in Example 1 9.29 g (0.031 mole) of (-)-N-[(4-methylphenyl) sulfonyl] -D-glutamic acid was carried out in the same manner as in Example 8 to obtain a solid. The obtained solid was recrystallized twice from ethanol to give more optically pure lecithin methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N- [ 6.47 g of (4-methylphenyl) sulfonyl] -D-glutamate were obtained.

m.p. : 151.0 ℃

Yield: 60.8%

¹ H-NMR (TFA-d ₁ ) ppm: 2.19-2.24 (m, 1H), 2.45-2.49 (m, 1H), 2.59 (s, 3H), 2.84 (t, 2H), 3.79 (br s, 2H ), 4.01-4.20 (m, 11H), 4.37-4.41 (m, 5H), 5.58 (br s, 1H), 7.55 (d, 2H), 7.61-7.72 (m, 9H), 7.94 (d, 2H)

[α] ²⁵ ₃₆₅ :-107.08 (c = 1, methanol)

Example 10 Preparation of Left-handed 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride (cetirizine dihydrochloride)

Priority methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N-[(4-methylphenyl) sulfonyl] prepared in Example 6. To 9.36 g (0.013 mole) of -L-glutamate, 94 ml of ethyl acetate were added, and 94 ml of 0.5 M aqueous sodium hydrogen carbonate solution was slowly added. After stirring for 1 hour, the organic phase was extracted and washed twice with 94 ml of 0.5 M aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate and the filtrate was concentrated.

The residue obtained by concentration was dissolved in 9.4 ml of methanol, and 14 ml of 1N aqueous sodium hydroxide solution was slowly added thereto. After reacting for 3 hours at room temperature, 80 ml of water was added and washed with 94 ml of ethyl acetate. 14 ml of 1N aqueous hydrochloric acid solution was added to the aqueous solution to maintain a pH of 4 to 5. The mixture was extracted three times successively with 94 ml of methylene chloride and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride and the organic phase was concentrated.

The residue obtained by concentration was dissolved in 94 ml of acetone at room temperature and 2.50 ml of concentrated hydrochloric acid was added. The precipitated solid was filtered, washed with a small amount of acetone and dried to enzymatic 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride 5.11 g was obtained.

m.p. : 216.7 ℃

Yield: 83.3%

¹ H-NMR (CD ₃ OD) ppm: 3.59 (br s, 6H), 3.93 (br s, 6H), 4.20 (d, 2H), 5.74 (br s, 1H), 7.39-7.50 (m, 5H) , 7.86-7.90 (m, 4H)

[α] ²⁵ ₃₆₅ :-12.49 (c = 1, water)

Optical Purity: 95% ee

Example 11 Preparation of Enzymatic 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride (cetirizine dihydrochloride)

Priority methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N-[(4-methylphenyl) sulfonyl] prepared in Example 7. 3.25 g (4.62 mmole) of -L-glutamate were carried out in the same manner as in Example 10 to determine left-handed 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 1.84 g of acetic acid dihydrochloride were obtained.

m.p. : 215.7 ℃

Yield: 86.3%

¹ H-NMR (CD ₃ OD) ppm: 3.57 (br s, 6H), 3.93 (br s, 6H), 4.20 (d, 2H), 5.74 (br s, 1H), 7.38-7.50 (m, 5H) , 7.86-7.90 (m, 4H)

[α] ²⁵ ₃₆₅ :-12.79 (c = 1, water)

Optical Purity: 99.6% ee

Example 12 Preparation of Preferred 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride (cetirizine dihydrochloride)

Left-handed methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N-[(4-methylphenyl) sulfonyl] prepared in Example 8] To 9.10 g (0.013 mole) of -D-glutamate, 91 ml of ethyl acetate was added, and 91 ml of 0.5 M aqueous sodium hydrogen carbonate solution was slowly added. After stirring for 1 hour, the organic phase was extracted and washed twice with 91 ml of 0.5 M aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, washed with ethyl acetate and the filtrate was concentrated.

The residue obtained by concentration was dissolved in 9.1 ml of methanol, and 13.6 ml of 1N aqueous sodium hydroxide solution was slowly added thereto. After reacting for 3 hours at room temperature, 77.4 ml of water was added and washed with 91 ml of ethyl acetate. 13.6 ml of 1N aqueous hydrochloric acid solution was added to the aqueous solution to maintain a pH of 4 to 5. The mixture was extracted three times successively with 91 ml of methylene chloride and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride and the organic phase was concentrated.

The residue obtained by concentration was dissolved in 91 ml of acetone at room temperature and 2.44 ml of concentrated hydrochloric acid was added. The precipitated solid was filtered, washed with a small amount of acetone and dried to give priority to 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride 5.27 g was obtained.

m.p. : 217.3 ℃

Yield: 88.3%

¹ H-NMR (CD ₃ OD) ppm: 3.57 (br s, 6H), 3.92 (br s, 6H), 4.21 (d, 2H), 5.71 (br s, 1H), 7.38-7.49 (m, 5H) , 7.85-7.89 (m, 4H)

[α] ²⁵ ₃₆₅ : + 12.25 (c = 1, water)

Optical Purity: 95% ee

Example 13. Preparation of Priority 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride (cetirizine dihydrochloride)

Left-handed methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate-N-[(4-methylphenyl) sulfonyl] prepared in Example 9] 4.00 g (5.68 mmole) of -D-glutamate were carried out in the same manner as in Example 12 to give priority to 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy ] 2.23 g of acetic acid dihydrochloride were obtained.

m.p. : 215.6 ℃

Yield: 85.0%

¹ H-NMR (CD ₃ OD) ppm: 3.58 (br s, 6H), 3.93 (br s, 6H), 4.20 (d, 2H), 5.74 (br s, 1H), 7.38-7.50 (m, 5H) , 7.86-7.90 (m, 4H)

[α] ²⁵ ₃₆₅ : + 12.81 (c = 1, water)

Optical Purity: 99.2% ee

Example 14. Recovery of (-)-N-[(4-methylphenyl) sulfonyl] -D-glutamic acid

Left-handed methyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate N-[(4-methylphenyl) sulfonyl] in the reaction of Example 12 91 ml of ethyl acetate was added to 9.10 g (0.013 mole) of -D-glutamate, 91 ml of 0.5 M aqueous sodium bicarbonate solution was slowly added thereto, the mixture was stirred for 1 hour, followed by extraction of the organic phase. 47 ml of aqueous solution was added to adjust the pH to 3 or less and extracted three times in succession with 50 ml of ethyl acetate. The combined organic phases were washed with 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate and the organic phase was concentrated. 50 ml of diisopropyl ether was added to the residue to crystallize. The resulting solid was filtered and washed with a small amount of diisopropyl ether to give 3.19 g of the desired (-)-N-[(4-methylphenyl) sulfonyl] -D-glutamic acid.

m.p. : 127.2 ℃

Yield (recovery rate): 81.9%

¹ H-NMR (DMSO-d ₆ ) ppm: 1.56-1.68 (m, 1H), 1.76-1.87 (m, 1H), 2.18 (t, 2H), 2.35 (s, 3H), 3.72 (br s, 1H ), 7.34 (d, 2H), 7.62 (d, 2H), 8.06 (d, 1H), 12.40 (br s, 2H)

[α] ²⁰ ₅₈₉ :-12.91 (c = 5, acetone)

The preparation method of the present invention utilizes glutamate of 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid ester to form cetirizine in racemic form or By purely optical resolution of the salts in high yield, an optically active cetirizine or salt thereof can be prepared.

Claims (9)

(a) reacting an optically active compound of formula 1 with a base to produce an optically active compound of formula 2a; And (b) hydrolyzing the compound of Formula 2a, to a method for preparing optically active cetirizine or a salt thereof: <Formula 1> <Formula 2a> In the formula, R ¹ is a C ₁ ~C ₆ alkyl, R ² is an amino protecting group. The method according to claim 1, wherein the amino protecting group is phenylsulfonyl or (4-methylphenyl) sulfonyl. The method according to claim 1, wherein the base is sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, or potassium carbonate. The method of claim 1, further comprising reacting the hydrolysis product of the compound of Formula 2a with hydrochloric acid in an organic solvent. The method according to any one of claims 1 to 4, wherein the optically active compound of formula (1) is obtained by reacting a compound of formula (2b) and an optically active compound of formula (3) in a racemic body. : <Formula 2b> <Formula 3> Wherein R ¹ and R ² are as defined in claim 1. The method according to claim 5, wherein the reaction of the compound of Formula 2b and the optically active compound of Formula 3 is carried out in an alcohol selected from the group consisting of methanol, ethanol, and isopropanol or a mixed solvent of alcohol and water. Manufacturing method. The method of claim 5, further comprising recrystallizing the optically active compound of formula 1 in an alcohol selected from the group consisting of methanol, ethanol, and isopropanol or a mixed solvent of alcohol and water. Optically active compound of formula (I): <Formula 1> Wherein R ¹ and R ² are as defined in claim 1. 9. A compound according to claim 8, wherein said amino protecting group is phenylsulfonyl or (4-methylphenyl) sulfonyl.