KR20090025830A - Method for preparing (r)-1-[(4-chlorophenyl)phenylmethyl]piperazine and salts thereof - Google Patents

Abstract

A manufacturing method of (R)-1-[(4-chlorophenyl) phenylmethyl piperazine] is provided to have high yield and high optical purity, to be conveniently manufactured and to be usefully used as intermediate. A manufacturing method of (R)-1-[(4-chlorophenyl) phenylmethyl piperazine] indicated as a chemical formula 1 or salts thereof comprises steps of: manufacturing a compound of a chemical formula 4 by reacting (R)-(4-chlorophenyl) phenylmethyl amine indicated as a chemical formula 2 with a compound of a chemical formula 3 under presence of organic base; and hydrolyzing the manufactured compound of the chemical formula 4 using strong acid or strong base. In the chemical formula 3 and the chemical formula 4: R is hydrogen, C1-4 alkyl, C1-4 alkoxy, C3-10 aryl, C3-10 aryloxy or benzyloxy; X is halogen, methanesulfonyl or p-toluenesulfonyl.

Description

(R) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof preparation method {METHOD FOR PREPARING (R) -1-[(4-CHLOROPHENYL) PHENYLMETHYL] PIPERAZINE AND SALTS THEREOF}

The present invention relates to a process for preparing ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof, which is a major intermediate for the preparation of the antihistamine levocetirizine useful for the treatment of allergic rhinitis and the like.

( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of the following formula (1) is an antihistamine levocetirizine useful for the treatment of allergic rhinitis (chemical name: ( R ) -2- [2- [4-[(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid, a sedentary isomer of cetirizine) is known as the main intermediate used in the manufacturing process:

British Patent Nos. 2,225,321 and 5,478,941 disclose various methods of preparing levocetirizine from an optically active compound of Formula 1. For reference, similarly, US Pat. No. 4,525,358 discloses a process for preparing cetirizine from the racemate of Formula 1 (corresponding to the compound of Formula 1a in Scheme 1 below).

British Patent No. 2,225,321 discloses a compound of Formula 1 by optically dividing (±) -1-[(4-chlorophenyl) phenylmethyl] piperazine of Formula 1a with L-(+)-tartrate. A method is disclosed (see Scheme 1 below). However, this method has the disadvantage that the desired product is obtained in a very low yield of about 6.5%:

In addition, US Pat. No. 5,478,941 discloses a sulfonamide compound of Chemical Formula 6 by reacting ( R )-(chlorophenyl) phenylmethylamine of Chemical Formula 2 having an optical activity with a compound of Chemical Formula 5, and then catalyst An improved process for the preparation of compounds of formula 1 by reacting with hydrobromic acid in acetic acid in the presence is disclosed (see Scheme 2 below). However, this method requires an excess of 4-hydroxybenzoic acid, has the inconvenience of preparing by dissolving hydrobromic acid in acetic acid, which is very difficult to dispose of even after use:

Document 1 GB 2225321 (UCB Pharmaceuticals, Inc.) 1990. 5.30.

US Pat. No. 54,789,41 (UCB Pharmaceuticals, Inc.) 1995.12.26.

US Pat. No. 4,525,358 (UCB Pharmaceuticals, Inc.) June 25, 1985.

Accordingly, it is an object of the present invention to conveniently prepare ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of Formula 1 which is usefully used as an intermediate in the preparation of levocetirizine with high yield and high optical purity. To provide a way.

In order to achieve the above object, the present invention

(1) preparing a compound of formula 4 by reacting ( R )-(4-chlorophenyl) phenylmethylamine of formula 2 with a compound of formula 3 in the presence of an organic base; And

(2) hydrolyzing the compound of formula 4 prepared in step (1) with a strong acid or strong base

It provides a process for the preparation of ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof of Formula 1 comprising:

[Formula 1]

Where

R is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-10 aryl, C _3-10 aryloxy or benzyloxy;

X is halogen, methanesulfonyl or p-toluenesulfonyl.

According to the method of the present invention, ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of Formula 1 or a salt thereof which is usefully used as an intermediate in the preparation of levocetirizine, an antihistamine, can be easily used. Reagents available are readily available in high yield and high optical purity of 99% or more.

Hereinafter, the method for preparing the compound of Formula 1 according to the present invention will be described in detail for each step.

Step (1)

In step (1), ( R )-(4-chlorophenyl) phenylmethylamine of formula (2) is reacted with a compound of formula (3) in the presence of an organic base to prepare a compound of formula (4), which reaction is carried out at reflux of the solvent at 60 ° C. Can be carried out at a temperature.

Examples of the organic base used in the present invention include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine and mixtures thereof. It can be used in an amount of 1 to 5 molar equivalents relative to 1 molar equivalent of the compound.

The compound of Formula 3 may be used in an amount of 1 to 1.5 molar equivalents relative to 1 molar equivalent of the compound of Formula 2.

The reaction of step (1) may be carried out in one or more organic solvents selected from the group consisting of acetone, acetonitrile, ethyl acetate, tetrahydrofuran, benzene, toluene and N, N-dimethylformamide, but without organic solvents. It may be desirable to.

In the compounds of the formulas (3) and (4), R may preferably be hydrogen, methyl, phenyl, methoxy, ethoxy, phenoxy or benzyloxy.

Step 2

In step (2), the compound of formula 4 prepared in step (1) is hydrolyzed with a strong acid or strong base to prepare a desired compound, which may be carried out at a reflux temperature of 60 ° C. to a solvent.

The strong acid used in the present invention may be used in an amount of 3 to 10 molar equivalents relative to 1 molar equivalent of the compound of Formula 4, and the strong base may be used in an amount of 1 to 5 molar equivalents relative to 1 molar equivalent of the compound of Formula 4. As the strong acid or strong base, hydrochloric acid, sodium hydroxide or potassium hydroxide is suitable.

The reaction of step (2) can be carried out in one or more solvents selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane and water, which solvent is of formula It is suitable to use in an amount of 3 to 30 ml relative to 1 g of the compound of 4.

The ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of Formula 1 thus prepared is crystallized in hexane or the like to obtain a free base having a melting point of about 90 ° C., or hydrochloric acid or bromic acid in an organic solvent. And inorganic acids such as sulfuric acid and phosphoric acid, or organic acids such as maleic acid, fumaric acid, oxalic acid, tartaric acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, naphthalenesulfonic acid and the like can be obtained in the form of acid addition salts. At this time, examples of the organic solvent to be used include ethyl ether, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, benzene, toluene, methanol, ethanol, isopropanol, and mixtures thereof. It may be 1 to 3 molar equivalents relative to 1 molar equivalent of the compound.

The ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine and the salts thereof of Formula 1 prepared according to the process of the invention have a high optical purity of at least 99%. Thus, it can be used as an intermediate to prepare optically pure levocetirizine according to or similar to those disclosed in British Patent Nos. 2,225,321, US Pat. Nos. 4,525,358, 5,478,941 and 5,698,558 and the like.

On the other hand, the present invention provides a compound of formula (4), which is used as an intermediate in the method for preparing a compound of formula (1) as described above, wherein the compound of formula (4) is a novel optically pure compound that is higher than 99% during the manufacturing process Obtained with optical purity:

[Formula 4]

Wherein R is as defined above.

By hydrolyzing the intermediate having such high optical purity, the compound of formula (1) and further desired levocetirizine can be easily prepared with optical purity of 99% or more.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.

The optical purity of each compound described in the Examples is expressed from the peak area of the left and right isomers separated by liquid chromatography using a chiral column such as Chiralcel OD-R. Calculated by 1.

Optical purity of the isomer (%) = A _L / (A _L + A _D ) × 100

Wherein A _L is The peak area of the left isomer, and A _D is the peak area of the preferential isomer.

Example 1: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4- (methoxycarbonyl) piperazine (Compound in which R is methoxy in Formula 4)

2.0 g of ( R ) -4-chlorophenylmethylamine was dissolved in 3.8 mL of N, N-diisopropylethylamine, 1.8 g of methyl bis (2-chloroethyl) carbamate was added and refluxed for 4 hours. The reaction solution was cooled to room temperature, 20 mL of water was added thereto, and extracted with 30 mL of dichloromethane. The organic layer was washed with 10 ml of 1.5 N aqueous hydrochloric acid solution and 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.3 g (yield: 72%) of the title compound as a foam.

Optical purity: 99.7%

Specific light intensity: [α] _D ²⁵ = -2.43 (c = 1.0, MeOH)

¹ H-NMR (CDCl ₃ , ppm): δ 7.4 (m, 4H), 7.2 (m, 5H), 4.2 (s, 1H), 3.7 (s, 3H), 3.5 (m, 4H), 2.4 (m , 4H).

IR (KBr, cm ⁻¹ ): 2857, 2819, 1696, 1491, 1444, 1404, 1289, 1243, 1124, 1090, 1001, 770, 758, 538, 495.

Example 2: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4- (ethoxycarbonyl) piperazine (Compound in which R is ethoxy in Formula 4)

40.0 g of ( R ) -4-chlorophenylmethylamine was dissolved in 76 ml of N, N-diisopropylethylamine, and 38.0 g of ethyl bis (2-chloroethyl) carbamate was added and refluxed for 4 hours. The reaction solution was cooled to room temperature, 400 ml of water was added, and the mixture was extracted with 600 ml of dichloromethane. The organic layer was washed with 200 ml of 1.5N aqueous hydrochloric acid solution and 400 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of a foam. This was crystallized in ethyl acetate and hexane to give 52 g (yield: 80%) of the title compound as a white powder.

Optical purity: 99.7%

Melting Point: 111 ~ 112 ℃

Specific light intensity: [α] _D ²⁵ = -1.60 (c = 1.0, MeOH)

¹ H-NMR (CDCl ₃ , ppm): δ 7.4 (m, 4H), 7.3 to 7.2 (m, 5H), 4.2 (s, 1H), 4.1 (q, 2H), 3.5 (m, 4H), 2.4 (m, 4H), 1.3 (t, 3H).

IR (KBr, cm ⁻¹ ): 2986, 2858, 2815, 1691, 1681, 1487, 1430, 1289, 1241, 1124, 1089, 993, 767, 758, 701, 544.

Example 3: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4- (phenyloxycarbonyl) piperazine (Compound in which R is phenoxy in Formula 4)

2.0 g ( R ) -4-chlorophenylmethylamine was dissolved in 3.8 mL of triethylamine, 2.6 g of phenyl bis (2-chloroethyl) carbamate were added and refluxed for 5 hours. The reaction solution was cooled to room temperature, 20 mL of water was added thereto, and then extracted with 30 mL of dichloromethane. The organic layer was washed with 10 mL of 1.5 N aqueous hydrochloric acid solution and 30 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.1 g (yield: 57%) of the title compound as a foam.

¹ H-NMR (CDCl ₃ , ppm): δ 7.4-7.1 (m, 14H), 4.4 (s, 1H), 3.9 (m, 2H), 3.8 (m, 2H), 2.6 (m, 4H).

IR (KBr, cm ⁻¹ ): 3377, 2814, 1722, 1697, 1594, 1490, 1454, 1426, 1291, 1241, 1211, 1000, 755, 691, 536, 507.

Example 4: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4- (benzyloxycarbonyl) piperazine (Compound in which R is benzyloxy in formula 4)

2.0 g of ( R ) -4-chlorophenylmethylamine was dissolved in 3.2 ml of triethylamine, 2.5 g of benzyl bis (2-chloroethyl) carbamate were added and refluxed for 18 hours. The reaction solution was cooled to room temperature, 20 mL of water was added thereto, and extracted with 30 mL of dichloromethane. The organic layer was washed with 10 ml of 1.5 N aqueous hydrochloric acid solution and 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.0 g (yield: 51%) of the title compound as a foam.

¹ H-NMR (CDCl ₃ , ppm): δ 7.4-7.2 (m, 14H), 5.1 (s, 2H), 4.2 (s, 1H), 3.5 (m, 4H), 2.4 (m, 4H).

IR (KBr, cm ⁻¹ ): 3374, 2811, 1701, 1489, 1453, 1430, 1290, 1238, 1120, 1088, 1000, 804, 758, 698, 529.

Example 5: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4-acetylpiperazine (Compound in which R is methyl in Formula 4)

2 g of ( R ) -4-chlorophenylmethylamine was dissolved in 3.8 ml of N, N-diisopropylethylamine, 1.7 g of N, N-bis (2-chloroethyl) acetamide was added and refluxed for 1 hour. . The reaction solution was cooled to room temperature, 20 ml of water was added, and extracted with 30 ml of dichloromethane. The organic layer was washed with 10 ml of 1.5N aqueous hydrochloric acid solution and 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 1.6 g (yield: 54%) of the title compound as a foam.

Optical purity: 99.7%

Specific light intensity: [α] _D ²⁵ = -0.45 (c = 1.0, MeOH)

¹ H-NMR (CDCl ₃ , ppm): δ 7.4 ~ 7.2 (m, 9H), 4.2 (s, 1H), 3.6 (m, 2H), 3.5 (m, 2H), 2.4 (m, 4H), 2.1 (s, 3 H).

IR (KBr, cm ⁻¹ ): 3427 (br), 2964, 2760, 1646, 1489, 1425, 1261, 1246, 1088, 997, 803, 758, 670.

Example 6: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4-benzoylpiperazine (Compound in which R is phenyl in Formula 4)

2.0 g of ( R ) -4-chlorophenylmethylamine was dissolved in 3.8 ml of N, N-diisopropylethylamine, 2.3 g of N, N-bis (2-chloroethyl) benzamide was added and refluxed for 1 hour. I was. The reaction solution was cooled to room temperature, 20 mL of water was added thereto, and extracted with 30 mL of dichloromethane. Washed with 10 ml of 1.5 N aqueous hydrochloric acid solution and 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.26 g (yield: 63%) of the title compound as a foam.

¹ H-NMR (CDCl ₃ , ppm): δ 7.3 to 7.2 (m, 14H), 4.2 (s, 1H), 3.7 (m, 2H), 3.4 (m, 2H), 2.4 (m, 2H), 2.3 (m, 2 H).

IR (KBr, cm ⁻¹ ): 2807, 1634, 1488, 1430, 1290, 1264, 1088, 1014, 998, 758, 710, 699, 529.

Example 7: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] -4-formylpiperazine (Compound in which R is hydrogen in Formula 4)

2.0 g of ( R ) -4-chlorophenylmethylamine was dissolved in 3.8 ml of N, N-diisopropylethylamine, 1.6 g of N, N-bis (2-chloroethyl) formamide was added and refluxed for 1 hour. I was. The reaction solution was cooled to room temperature, 20 mL of water was added thereto, and extracted with 30 mL of dichloromethane. The organic layer was washed with 10 ml of 1.5 N aqueous hydrochloric acid solution and 30 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.7 g (yield: 60%) of the title compound as a foam.

Optical purity: 99.7%

Specific light intensity: [α] _D ²⁵ = -2.10 (c = 1.0, MeOH)

¹ H-NMR (CDCl ₃ , ppm): δ 8.0 (s, 1H), 7.4-7.2 (m, 9H), 4.3 (s, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 2.4 (m, 4 H).

IR (KBr, cm ⁻¹ ): 2910, 2885, 2825, 1672, 1490, 1434, 1394, 1284, 1227, 1192, 1140, 1089, 1071, 1020, 817, 758, 720, 702, 537, 504.

Example 8: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine

40 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] -4- (ethoxycarbonyl) piperazine obtained in Example 2 was dissolved in 280 ml of isopropanol and 31.2 g of potassium hydroxide was added. It was refluxed for hours. The reaction solution was distilled under reduced pressure to remove the solvent, and 120 mL of dichloromethane and 120 mL of 1.5N hydrochloric acid solution were added to the residue, followed by layer separation. The aqueous layer was taken, adjusted to pH 10 with 5N-sodium hydroxide solution and extracted with 280 ml of dichloromethane. The organic layer was washed with 120 ml of brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 28.8 g (yield: 90%) of the title compound as a foam. 14.4 g of foam was crystallized in hexane to give 13.0 g of pure white crystals.

Optical purity: 99.7%

Specific light intensity: [α] _D ²⁵ = -21.2 (c = 1.0, MeOH)

Melting Point: 90 ~ 92 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ , ppm): δ 7.4 (m, 4H), 7.2 (m, 5H), 4.2 (s, 1H), 2.9 (m, 4H), 2.3 (m, 4H).

IR (KBr, cm ⁻¹ ): 3304, 2952, 2907, 2792, 1486, 1452, 1124, 1090, 1014, 998, 797, 755, 718, 692, 549, 506.

Example 9: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine

To 4.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] -4- (ethoxycarbonyl) piperazine obtained in Example 2, 28 ml of 6N hydrochloric acid was added and refluxed for 12 hours. The reaction solution was adjusted to pH 10 with 5N sodium hydroxide solution and extracted with 50 mL of dichloromethane. The organic layer was washed with 30 mL of brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.5 g (yield: 78%) of the title compound as a foam.

Optical purity: 99.7%.

Example 10: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine

To 1.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] -4-acetylpiperazine obtained in Example 5, 10 ml of 1N hydrochloric acid was added and refluxed for 4 hours. The reaction solution was cooled to room temperature, adjusted to pH 10 with 1N-sodium hydroxide solution, and extracted with 30 ml of ethyl acetate. The organic layer was washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.75 g (yield: 85%) of the title compound as a foam.

Optical purity: 99.7%.

Example 11: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine

To 1.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] -4-formylpiperazine obtained in Example 7, 20 ml of a 1 N-hydrochloric acid methanol solution was added to dissolve and refluxed for 1 hour. . The reaction solution was concentrated under reduced pressure to remove methanol, and the residue was dissolved in water, adjusted to pH 10 with 1N sodium hydroxide and extracted with 30 ml of ethyl acetate. The organic layer was washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.8 g (yield: 89%) of the title compound as a foam.

Optical purity: 99.7%.

Example 12: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine disulfate

3.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine foam prepared in Example 8 was dissolved in 30 ml of acetone, and then 2.1 g of sulfuric acid was added and stirred at room temperature for 3 hours. The resulting crystals were filtered and dried to yield 4.8 g (yield: 95%) of the title compound as white crystals.

Optical purity: 99.8%

Specific light intensity: [α] _D ²⁵ = -3.0 (c = 1.0, MeOH)

Melting Point: 206 ~ 208 ℃ (Decomposition)

¹ H-NMR (DMSO-d ₆ , ppm): δ 7.6 (m, 4H), 7.4-7.3 (m, 5H), 5.1 (s, 1H), 3.3 (m, 4H), 2.9 (m, 4H) .

IR (KBr, cm ⁻¹ ): 3417 (br), 2909, 2558, 1624, 1494, 1456, 1430, 1314, 1230, 1067, 1014, 852, 840, 601, 587.

Example 13: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine dimaleate

3.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine foam prepared in Example 8 was dissolved in 30 ml of ethyl acetate, and then 2.4 g of maleic acid was added thereto, followed by stirring at room temperature for 3 hours. . The resulting crystals were filtered and dried to give 5.3 g (yield: 98%) of the title compound as white crystals.

Optical purity: 99.8%

Specific light intensity: [α] _D ²⁵ = -8.2 (c = 1.0, MeOH)

Melting Point: 142 ~ 143 ℃ (Decomposition)

¹ H-NMR (CDCl ₃ , ppm): δ 7.4-7.2 (m, 9H), 6.2 (s, 4H), 4.4 (s, 1H), 3.2 (m, 4H), 2.1 (m, 4H).

IR (KBr, cm ⁻¹ ): 3433 (br), 2537, 1704, 1624, 1577, 1491, 1454, 1431, 1386, 1351, 1199, 1092, 994, 863, 757, 722, 703, 646.

Example 14: ( R Preparation of) -1-[(4-chlorophenyl) phenylmethyl] piperazine i-toluenesulfonate

3.0 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine foam prepared in Example 8 was dissolved in 30 ml of acetone, followed by addition of 4.0 g of p-toluenesulfonic acid and stirring at room temperature for 3 hours. It was. The resulting crystals were filtered and dried to give 6.1 g (yield: 93%) of the title compound as white crystals.

Optical purity: 99.8%

Specific light intensity: [α] _D ²⁵ = -7.4 (c = 1.0, MeOH)

Melting Point: 213 ~ 217 ℃ (Decomposition)

¹ H-NMR (DMSO-d ₆ , ppm): δ 7.5 ~ 7.2 (m, 13H), 7.1 (m, 4H), 5.0 (s, 1H), 3.3 (m, 4H), 2.8 (m, 4H) , 2.3 (s, 6H).

IR (KBr, cm ⁻¹ ): 3442 (br), 2981, 2681, 1494, 1446, 1247, 1159, 1123, 1033, 1010, 680, 567.

Reference Example 1: ( R Preparation of Levocetirizine Dihydrochloride from) -1-[(4-chlorophenyl) phenylmethyl] piperazine (Compound of Formula 1)

10 g of ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine prepared in Example 8 was dissolved in 60 ml of dimethylformamide, and 7 g of ethyl 2- (2-chloroethoxy) acetate and di 7 ml of isopropylethylamine and a catalytic amount (0.1 g) of sodium iodide were sequentially added, and the temperature was raised to reflux for 4 hours. After the reaction solution was cooled to room temperature, 200 ml of water was added thereto, followed by extraction with 200 ml of ethyl acetate. The organic layer was washed with 150 ml of water and 100 ml of brine, respectively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give ( R ) -2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-pipera. 11.6 g (yield: 80%) of genyl] ethoxy] acetic acid ethyl ester was obtained.

11.6 g of ( R ) -2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid ethyl ester obtained above was dissolved in 80 ml of ethanol, and To the potassium hydroxide was added 3.1g and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, 50 ml of water was added thereto, and the pH was adjusted to 4-5 with 3N hydrochloric acid. Extracted with 60 ml of dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain ( R ) -2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid, 10.6 g (yield: 100%) of levocetirizine was obtained as a foam.

After dissolving 10.6 g of the obtained levocetirizine foam in 120 ml of acetone, 1 g of activated carbon was added and stirred at 50 ° C. for 30 minutes. After removing activated carbon using celite, 4.8 ml of concentrated hydrochloric acid was slowly added dropwise to the filtrate, and the mixture was stirred at room temperature for 6 hours. The mixture was cooled to 0-5 [deg.] C. and stirred for at least 1 hour, then the resulting white solid was filtered and washed with acetone. The resulting solid was dried at 40 ° C. to give 8.5 g of levocetirizine dihydrochloride (yield: 67%).

Optical purity: 99.8%

Specific light intensity: [α] ₃₆₅ ²⁵ = +12.85 (c = 1.0, H ₂ O)

Melting Point: 216 ~ 217 ℃ (Decomposition)

¹ H-NMR (D ₂ O, ppm): δ 7.5 (d, 2H), 7.3 (m, 5H), 7.1 (d, 2H), 5.3 (s, 1H), 4.1 (s, 2H), 3.8 ( m, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.4 (m, 4H).

IR (KBr, cm ⁻¹ ): 3413 (br), 2948, 2371, 1745, 1496, 1456, 1434, 1384, 1356, 1320, 1183, 1137, 919, 845, 808, 758, 720, 700, 534.

Claims (11)

(1) preparing a compound of formula 4 by reacting ( R )-(4-chlorophenyl) phenylmethylamine of formula 2 with a compound of formula 3 in the presence of an organic base; And (2) hydrolyzing the compound of formula 4 prepared in step (1) with a strong acid or strong base ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof according to Formula 1 comprising: [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Where R is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-10 aryl, C _3-10 aryloxy or benzyloxy; X is halogen, methanesulfonyl or p-toluenesulfonyl. The method of claim 1, R of the compound of formula 3 or formula 4 used in step (1) is hydrogen, methyl, phenyl, methoxy, ethoxy, phenoxy or benzyloxy, ( R ) -1- Method for preparing [(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof. The method of claim 1, Formula is characterized in that the organic base of step (1) is selected from the group consisting of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picoline, lutidine and mixtures thereof ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of 1 or a salt thereof. The method of claim 1, In the step (1), characterized in that the organic base is used in an amount of 1 to 5 molar equivalents to 1 molar equivalent of the compound of the formula (2), ( R ) -1-[(4-chlorophenyl) phenyl Methyl] piperazine or a salt thereof. The method of claim 1, In step (2), ( R ) -1-[(4-chlorophenyl) phenylmethyl of Formula 1, characterized in that the strong acid is used in an amount of 3 to 10 molar equivalents to 1 molar equivalent of the compound of the formula (4). ] Process for preparing piperazine or salts thereof. The method of claim 1, In the step (2), characterized in that the strong base is used in an amount of 1 to 5 molar equivalents to 1 molar equivalent of the compound of formula 4, ( R ) -1-[(4-chlorophenyl) phenylmethyl of Formula 1 ] Process for preparing piperazine or salts thereof. The method of claim 1, ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of Formula 1, or a salt thereof, characterized in that the reaction of steps (1) and (2) is carried out at 60 ° C. to the reflux temperature of the solvent. Manufacturing method. The method of claim 1, Wherein the reaction of step (2) is carried out in one or more solvents selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane and water ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine of 1 or a salt thereof. The method of claim 1, The strong acid or strong base of step (2) is characterized in that hydrochloric acid, sodium hydroxide or potassium hydroxide, ( R ) -1-[(4-chlorophenyl) phenylmethyl] piperazine or a salt thereof. A compound of formula [Formula 4]

Where R is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-10 aryl, C _3-10 aryloxy or benzyloxy. The method of claim 10, R is hydrogen, methyl, phenyl, methoxy, ethoxy, phenoxy or benzyloxy.