Preparation and application of a levocetirizine hydrochloride intermediate

Abstract

The application discloses a preparation method and application of a levocetirizine hydrochloride intermediate, and a high-quality levocetirizine hydrochloride intermediate is obtained. The method comprises the following steps: taking di(2-chloroethyl)amine as a raw material, performing a formate esterification reaction, performing a (R)-(4-chlorophenyl)(phenyl)methylamine cyclization, and performing reduction to obtain the levocetirizine hydrochloride intermediate, and then performing a substitution reaction to generate the levocetirizine hydrochloride. The method is simple in operation, has less by-product, has a high yield, is easy in raw material obtaining, is low in cost, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing levocetirizine hydrochloride intermediate IV and its application. Background Technology

[0002] Levocetirizine hydrochloride: Chemical name: R-(-)2-[2-[4-[4-(chlorophenyl)benzyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, developed by UCB Pharma, was approved for marketing in the United States in 1995, followed by approval in Germany on January 3, 2001, and approval from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on October 27, 2010. It is marketed in Germany under the brand name Xyzal by UCB and GlaxoSmithKline (GSK). Levocetirizine hydrochloride is the levorotatory R-enantiomer of cetirizine hydrochloride, capable of blocking histamine receptors, and is a selective histamine H1 receptor antagonist. Clinically, it is mainly used to relieve allergic symptoms of allergic diseases, to relieve typical symptoms of hay fever, and can also be used to treat seasonal allergic rhinitis, perennial allergic rhinitis, chronic urticaria, allergic conjunctivitis, etc. Its structure is as follows:

[0003] WO2009065622A1 discloses a method for synthesizing levocetirizine hydrochloride. This route involves reacting compound 1 (di(2-chloroethyl)amine hydrochloride) with compound 2 (phenylcarbonyl chloride) via an amide reaction to obtain intermediate 3 (phenyl bis(2-chloroethyl)carbamate). This intermediate is then reacted with compound 4 ((4-chlorophenyl)(phenyl)methylamine) and DIPEA under reflux to undergo a substitution and cyclization reaction to obtain intermediate 5 (4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-carboxylic acid phenyl ester). This intermediate is then refluxed with NaOH in isopropanol and hydrolyzed to generate intermediate 6 (1-((4-chlorophenyl)(phenyl)methyl)piperazine). Further reflux with L-tartaric acid in ethanol followed by NaOH treatment and resolution yields intermediate 7 ((R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine). Finally, reaction with compound 8 (2-(2-chloroethoxy)acetonitrile) via a substitution reaction yields intermediate 9. (R)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetonitrile) was finally hydrolyzed by heating in 37% HCl to form salt, yielding product 10 ((R)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetic acid dihydrochloride). In this process route, intermediate 6 is resolved to give intermediate 7 with a low yield (12.70%). The product 10 is obtained after 6 steps of reaction, resulting in a long synthetic route and a low overall yield (7.30%). Therefore, this route is not suitable for industrial production. The specific reaction route is as follows:

[0004] WO2009057133A2 discloses a method for synthesizing levocetirizine hydrochloride. This route involves a reduction reaction of (R)-1-phenylethanolamine with 2-chloroacetyl chloride to obtain the intermediate (R)-2-chloro-N-(1-phenylethyl)acetamide, followed by a substitution reaction with 2,2',2''-nitrotriethanol to obtain the intermediate (R)-2-(2-(bis(2-hydroxyethyl)amino)ethoxy)-N-(1-phenylethyl)acetamide, which is then reacted with MsCl in DCM to obtain the intermediate (R)-((2-(2-oxo-2-((1-phenylethyl)amino)ethoxy)ethyl)azadiyl)bis(ethane-2,1-diyl)dimethylsulfonate). The reaction of (S)-(4-chlorophenyl)(phenyl)methylamine with toluene via heating yields the intermediate 2-(2-(4-((R)-(4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)-N-((R)-1-phenylethyl)acetamide via cyclization after substitution in toluene. Under acidic conditions, the amide bond is hydrolyzed to give the intermediate (R)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetic acid. Finally, under acidic conditions, salt formation gives the product (R)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetic acid dihydrochloride. This process is lengthy, has low yields, consumes a large amount of reagents, and is cumbersome, making it unsuitable for scale-up. The specific reaction route is as follows:

[0005] WO2009062036A2 discloses a synthetic method for levocetirizine hydrochloride. This route involves reacting (R)-(4-chlorophenyl)(phenyl)methylamine with N,N-bis(2-chloroethyl)-4-methoxybenzenesulfonamide in DIPEA at 125°C, followed by a substitution and cyclization reaction to obtain the intermediate (R)-1-((4-chlorophenyl)(phenyl)methyl)-4-((4-methoxyphenyl)sulfonyl)piperazine. This intermediate is then reacted with HBr and acetic acid at 70°C, and the mixture is treated with a 40% NaOH aqueous solution to obtain... The intermediate (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine reacts with 2-chloroethanol via a substitution reaction to give the intermediate (R)-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)methanol, which then reacts with sodium 2-chloroacetate via a substitution reaction to give the product (R)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetic acid dihydrochloride). The deprotection of the p-toluenesulfonyl group requires the use of hydrobromic acid, which is highly corrosive, irritating, and extremely toxic. The specific reaction route is as follows:

[0006] US patent 2007142400A1 discloses a synthetic method for levocetirizine hydrochloride. This route involves reacting (R)-(4-chlorophenyl)(phenyl)methylamine with N,N-bis(2-chloroethyl)-4-methoxybenzenesulfonamide in the presence of DIPEA, followed by a substitution and cyclization reaction to yield the intermediate (R)-1-((4-chlorophenyl)(phenyl)methyl)-4-((4-methoxyphenyl)sulfonyl)piperazine. The reaction is then carried out in HBr and acetic acid at 70°C, followed by PHAB treatment to obtain the intermediate (R)-1-((4-)- ... (S)-2-(2-(2-chlorophenyl)(phenyl)methyl)piperazine, methyl 2-(2-chloroethoxy)acetate, Na₂CO₃, and KI are refluxed in toluene, followed by the addition of maleic acid and methanol under reflux to yield the intermediate (S)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-yl)ethoxy)acetate maleate. Finally, hydrolysis under alkaline conditions yields the product (S)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazine-1-yl)ethoxy)acetate dihydrochloride. The third step of this process has a low yield and is not suitable for scale-up production. The specific reaction route is as follows: Summary of the Invention

[0007] The technical problem to be solved by this invention is as follows: In the process of removing the piperazine protecting group from intermediate IV, in order to improve efficiency, reduce the use of harmful solvents and simplify the operation for industrial production, this invention selects the formyl group for protection. The raw materials required by this invention are readily available, the operation is simple, the reaction conditions are mild, and there is less waste. Therefore, it has great implementation value and social and economic benefits. At the same time, it avoids the use of phase transfer catalysts and overcomes the disadvantages of low resolution yield, poor selectivity, low yield and high cost.

[0008] The specific solution of the present invention is as follows: The present invention comprises the following steps: Compound I (di(2-chloroethyl)amine) reacts with acetic anhydride to generate compound II, which then undergoes cyclization with (R)-(4-chlorophenyl)(phenyl)methylamine, followed by hydrolysis to prepare intermediate IV.

[0009] Step 1: Compound I (di(2-chloroethyl)amine) reacts with formic acid and anhydride in a one-pot reaction to generate intermediate II; Step 2: Intermediate II reacts with (R)-(4-chlorophenyl)(phenyl)methylamine under weakly basic conditions via a substitution and cyclization reaction to yield intermediate III; Step 3: Intermediate III is reacted with stirring in an acidic solution to obtain intermediate IV.

[0010] Furthermore, in step 1, the molar ratio of compound I to formic acid is 1:1 to 4, preferably 1:2; Furthermore, the reaction temperature in step 1 is 10~50℃, preferably 20-30℃; Furthermore, in step 2, the molar ratio of (R)-(4-chlorophenyl)(phenyl)methylamine to intermediate II is 1:1 to 3, preferably 1:1.5; Furthermore, the weak base used in step 2 is TEA and DIPEA, with DIPEA being preferred; Furthermore, in step 3, the acid is either methanol hydrochloride or ethanol hydrochloride, preferably methanol hydrochloride; Furthermore, the reaction temperature in step 3 is 0-50℃, preferably 20-25℃.

[0011] Another aspect of the present invention uses the above-obtained intermediate IV to prepare levocetirizine hydrochloride, including... Step 1: Intermediate IV reacts with 2-chloroethanol under weakly alkaline conditions to generate intermediate V; Step 2: Intermediate V is dissolved in an organic solvent under alkaline conditions, and then reacted with sodium 2-chloroacetate to form a salt with hydrochloric acid to obtain levocetirizine hydrochloride.

[0012] The advantages of this invention compared to existing technologies are mainly reflected in the following aspects: It provides a novel method for synthesizing levocetirizine intermediates by reacting compound I (di(2-chloroethyl)amine) with acetic anhydride to generate compound II, followed by cyclization with (R)-(4-chlorophenyl)(phenyl)methylamine and reduction. The intermediate is then further synthesized via a substitution reaction to generate levocetirizine hydrochloride. This method avoids the use of phase transfer catalysts and overcomes the disadvantages of low resolution yield, poor selectivity, low overall yield, and high cost. Furthermore, it overcomes technical biases in the deprotection process of intermediate IV, increasing the yield of this step to approximately 90%. The operation is simple, the reaction conditions are mild, and waste is minimal, thus possessing significant practical value and socio-economic benefits. Specific Implementation

[0013] The technical solution of the present invention will be described below with specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0014] Example 1

[0015] 100 g (979 mmol) of acetic anhydride and 45.08 g (979 mmol) of formic acid were added to a 500 ml single-necked flask and stirred at room temperature for 6 h. Then, 139.1 g (979 mmol) of compound I was added and stirred at 20-30 °C for 12 h. The reaction mixture was dissolved in 200 ml of saturated NaHCO3 solution. The mixture was separated by stirring with 300 ml x 2 ml of dichloromethane to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and then distilled under reduced pressure. The fractions were collected (2 mmHg, 120-124 °C) to give 153 g of intermediate II as a pale yellow oil. Yield: 91.2%, purity: 98.5%.

[0016] 100 g (459.3 mmol) of intermediate (R)-(4-chlorophenyl)(phenyl)methylamine, 78 g (459.3 mmol) of intermediate II, and 178 g (1.377 mol) of DIPEA were added to a 1000 ml single-necked flask and dissolved in 500 ml of toluene. The mixture was stirred at 90 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 132 g of intermediate III as a white solid (yield: 91.3%, purity: 99.3%).

[0017] Add 100 g (317.6 mmol) of intermediate III and 200 ml of 2M hydrochloric acid-methanol solution to a 500 ml single-necked flask, and stir at 20-25 °C for 2 h. Evaporate the solvent by rotary evaporation to obtain 86 g of intermediate IV as a pale yellow oil, yield 94.7%, purity 98.0%.

[0018] Intermediate IV (80 g, 279.6 mmol), 2-chloroethanol (33.76 g, 419.4 mmol), and TEA (42.44 g, 419.4 mmol) were dissolved in 400 ml of toluene and added to a 500 ml single-necked flask. The mixture was stirred at 80 °C for 12 h. Two 300 ml solutions of drinking water were added, and the mixture was separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to give intermediate V (84 g, white solid, yield: 94.8%, purity: 99.0%). 80 g (265.1 mmol) of intermediate V and 73.27 g (530.2 mmol) of K₂CO₃ were dissolved in 200 mL of DMF in a 500 mL single-necked flask and stirred at 5 °C for 2 h. 46.32 g (397.65 mmol) of sodium 2-chloroacetate and 100 mL of methanol were added, and the mixture was stirred at 5 °C for 2 h. 265 mL of 2M hydrochloric acid-methanol solution was added, and a solid was washed out. The solid was collected by filtration and dried to give 118 g of levocetirizine hydrochloride (96.4% yield, 99.9% purity).

[0019] Example 2

[0020] 150 g (1.47 mol) of acetic anhydride and 101.39 g (2.2 mol) of formic acid were added to a 1000 ml single-necked flask and stirred at room temperature for 6 h. Then, 139.1 g (979 mmol) of compound I was added and stirred at 20-30 °C for 12 h. The reaction mixture was dissolved in 300 ml of saturated NaHCO3 solution. The mixture was separated by stirring with 400 ml x 2 ml of dichloromethane to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and then distilled under reduced pressure. The fractions were collected (2 mmHg, 120-124 °C) to obtain 158 g of intermediate II, a pale yellow oil. Yield: 94.8%, purity: 98.5%.

[0021] 100 g (459.3 mmol) of intermediate (R)-(4-chlorophenyl)(phenyl)methylamine, 156 g (918.6 mmol) of intermediate II, and 139.2 g (1.377 mol) of TEA were added to a 1000 ml single-necked flask and dissolved in 500 ml of toluene. The mixture was stirred at 90 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 128 g of intermediate III as a white solid (yield: 95.1%, purity: 99.1%).

[0022] Add 100 g (317.6 mmol) of intermediate III and 200 ml of 2M hydrochloric acid-ethanol solution to a 500 ml single-necked flask, and stir at 20-25 °C for 2 h. Evaporate the solvent by rotary evaporation to obtain 80 g of intermediate IV as a pale yellow oil (88% yield, 98.2% purity).

[0023] Intermediate IV (80 g, 279.6 mmol), 2-chloroethanol (33.76 g, 419.4 mmol), and TEA (42.44 g, 419.4 mmol) were dissolved in 400 ml of toluene and stirred at 80 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain intermediate V (84 g, white solid, yield: 94.8%, purity: 99.2%). 80 g (265.1 mmol) of intermediate V and 73.27 g (530.2 mmol) of K₂CO₃ were dissolved in 200 mL of DMF in a 500 mL single-necked flask and stirred at 5 °C for 2 h. 46.32 g (397.65 mmol) of sodium 2-chloroacetate and 100 mL of methanol were added, and the mixture was stirred at 5 °C for 2 h. 265 mL of 2M hydrochloric acid-methanol solution was added, and a solid was washed out. The solid was collected by filtration and dried to give 118 g of levocetirizine hydrochloride (96.4% yield, 99.9% purity).

[0024] Example 3

[0025] 150 g (1.47 mol) of acetic anhydride and 101.39 g (2.2 mol) of formic acid were added to a 1000 mL single-necked flask and stirred at 10 °C for 6 h. Then, 139.1 g (979 mmol) of compound I was added and stirred at 10 °C for 12 h. The reaction mixture was dissolved in 300 mL of saturated NaHCO3 solution. The mixture was separated by stirring with 400 mL of dichloromethane (400 mL x 2) to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and then distilled under reduced pressure. The fractions were collected (2 mmHg, 120-124 °C) to obtain 150 g of intermediate II as a pale yellow oil. Yield: 90.05%, purity: 98.5%.

[0026] 100 g (459.3 mmol) of intermediate (R)-(4-chlorophenyl)(phenyl)methylamine, 78 g (459.3 mmol) of intermediate II, and 139.2 g (1.377 mol) of TEA were added to a 1000 ml single-necked flask and dissolved in 500 ml of toluene. The mixture was stirred at 90 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 112 g of intermediate III as a white solid (yield: 77.1%, purity: 98.7%).

[0027] 100 g (317.6 mmol) of intermediate III and 200 ml of 2M hydrochloric acid-methanol solution were added to a 500 ml single-necked flask and stirred at 40 °C for 2 h. The solvent was evaporated by rotary evaporation to obtain 82 g of intermediate IV as a pale yellow oily substance, with a yield of 89% and a purity of 98.8%.

[0028] Intermediate IV (80 g, 279.6 mmol), 2-chloroethanol (33.76 g, 419.4 mmol), and TEA (42.44 g, 419.4 mmol) were dissolved in 400 ml of toluene and stirred at 80 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain intermediate V (84 g, white solid, yield: 94.8%, purity: 99.1%).

[0029] 80 g (265.1 mmol) of intermediate V and 73.27 g (530.2 mmol) of K₂CO₃ were dissolved in 200 mL of DMF in a 500 mL single-necked flask and stirred at 5 °C for 2 h. 46.32 g (397.65 mmol) of sodium 2-chloroacetate and 100 mL of methanol were added, and the mixture was stirred at 5 °C for 2 h. 265 mL of 2M hydrochloric acid-methanol solution was added, and a solid was washed out. The solid was collected by filtration and dried to give 118 g of levocetirizine hydrochloride (96.4% yield, 99.9% purity).

[0030] Example 4

[0031] 150 g (1.47 mol) of acetic anhydride and 101.39 g (2.2 mol) of formic acid were added to a 1000 mL single-necked flask and stirred at 50 °C for 6 h. Then, 139.1 g (979 mmol) of compound I was added and stirred at 50 °C for 12 h. The reaction mixture was dissolved in 300 mL of saturated NaHCO3 solution. The mixture was separated by stirring with 400 mL of dichloromethane (400 mL x 2) to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and then distilled under reduced pressure. The fractions were collected (2 mmHg, 120-124 °C) to obtain 130 g of intermediate II, a pale yellow oil. Yield: 78%, purity: 98.5%.

[0032] 100 g (459.3 mmol) of intermediate (R)-(4-chlorophenyl)(phenyl)methylamine, 78 g (459.3 mmol) of intermediate II, and 139.2 g (1.377 mol) of TEA were added to a 1000 mL single-necked flask and dissolved in 500 mL of toluene. The mixture was stirred at 90 °C for 12 h. Two 300 mL solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 112 g of intermediate III as a white solid (yield: 77.1%, purity: 98.5%).

[0033] Add 100 g (317.6 mmol) of intermediate III and 200 ml of 2M hydrochloric acid-methanol solution to a 500 ml single-necked flask, and stir at 20-25 °C for 2 h. Evaporate the solvent by rotary evaporation to obtain 82 g of intermediate IV as a pale yellow oil, yield 90.2%, purity 98.8%.

[0034] Intermediate IV (80 g, 279.6 mmol), 2-chloroethanol (33.76 g, 419.4 mmol), and TEA (42.44 g, 419.4 mmol) were dissolved in 400 ml of toluene and stirred at 80 °C for 12 h. Two 300 ml solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to give intermediate V (84 g, white solid, yield: 94.8%, purity: 99.0%).

[0035] 80 g (265.1 mmol) of intermediate V and 73.27 g (530.2 mmol) of K₂CO₃ were dissolved in 200 mL of DMF in a 500 mL single-necked flask and stirred at 5 °C for 2 h. 46.32 g (397.65 mmol) of sodium 2-chloroacetate and 100 mL of methanol were added, and the mixture was stirred at 5 °C for 2 h. 265 mL of 2M hydrochloric acid-methanol solution was added, and a solid was washed out. The solid was collected by filtration and dried to give 118 g of levocetirizine hydrochloride (96.4% yield, 99.9% purity).

[0036] Example 5

[0037] 150 g (1.47 mol) of acetic anhydride and 270.37 g (5.86 mol) of formic acid were added to a 1000 ml single-necked flask and stirred at room temperature for 6 h. Then, 139.1 g (979 mmol) of compound I was added and stirred at room temperature for 12 h. The reaction mixture was dissolved in 300 ml of saturated NaHCO3 solution. The mixture was separated by stirring with 400 ml x 2 ml of dichloromethane to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and then distilled under reduced pressure. The fractions were collected (2 mmHg, 120-124 °C) to obtain 155 g of intermediate II as a pale yellow oil. Yield: 93%, purity: 98.6%.

[0038] 100 g (459.3 mmol) of intermediate (R)-(4-chlorophenyl)(phenyl)methylamine, 234 g (1.378 mmol) of intermediate II, and 178 g (1.377 mol) of DIPEA were added to a 1000 mL single-necked flask and dissolved in 500 mL of toluene. The mixture was stirred at 90 °C for 12 h. Two 300 mL solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to give 132 g of intermediate III as a white solid (yield: 93%, purity: 99.3%).

[0039] Add 100 g (317.6 mmol) of intermediate III and 200 ml of 2M hydrochloric acid-methanol solution to a 500 ml single-necked flask, and stir at 20-25 °C for 2 h. Evaporate the solvent by rotary evaporation to obtain 82 g of intermediate IV as a pale yellow oil, yield 90.2%, purity 98.9%.

[0040] Intermediate IV (80 g, 279.6 mmol), 2-chloroethanol (33.76 g, 419.4 mmol), and TEA (42.44 g, 419.4 mmol) were dissolved in 400 mL of toluene and stirred at 80 °C for 12 h. Two 300 mL solutions of drinking water were added, stirred, and separated to obtain the organic phase. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography to obtain intermediate V (84 g, white solid, yield: 94.8%, purity: 99.2%).

[0041] 80 g (265.1 mmol) of intermediate V and 73.27 g (530.2 mmol) of K₂CO₃ were dissolved in 200 mL of DMF in a 500 mL single-necked flask and stirred at 5 °C for 2 h. 46.32 g (397.65 mmol) of sodium 2-chloroacetate and 100 mL of methanol were added, and the mixture was stirred at 5 °C for 2 h. 265 mL of 2M hydrochloric acid-methanol solution was added, and a solid was washed out. The solid was collected by filtration and dried to give 118 g of levocetirizine hydrochloride (96.4% yield, 99.9% purity).

Claims

1. A method for preparing a levocetirizine hydrochloride intermediate, characterized in that... The levocetirizine hydrochloride intermediate is (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine, characterized by comprising the following steps: Step 1: Compound I, di(2-chloroethyl)amine, reacts with formic acid and acetic anhydride in a one-pot reaction to generate intermediate II, wherein the molar ratio of compound I to formic acid is 1:1~4, and the reaction temperature is 10~50℃; Step 2: Intermediate II and (R)-(4-chlorophenyl)(phenyl)methylamine were reacted with toluene under weakly basic conditions and stirred at 90°C for 12 h to obtain intermediate III through a substitution and cyclization reaction. The molar ratio of (R)-(4-chlorophenyl)(phenyl)methylamine to intermediate II was 1:1~3, and the weak base was DIPEA. Step 3: Intermediate III was reacted in a hydrochloric acid-methanol solution at 20-25℃ to obtain intermediate IV (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine; 。 2. The preparation method according to claim 1, characterized in that: In step 1, the molar ratio of compound I to formic acid is 1:2, and the reaction temperature is 20-30℃.

3. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of (R)-(4-chlorophenyl)(phenyl)methylamine to intermediate II is 1:1.

5.

4. A method for preparing levocetirizine hydrochloride, characterized in that, Includes the following steps: Step 1: Compound I, di(2-chloroethyl)amine, reacts with formic acid and acetic anhydride in a one-pot reaction to generate intermediate II, wherein the molar ratio of compound I to formic acid is 1:1~4, and the reaction temperature is 10~50℃; Step 2: Intermediate II and (R)-(4-chlorophenyl)(phenyl)methylamine were reacted with toluene under weakly basic conditions and stirred at 90°C for 12 h to obtain intermediate III through a substitution and cyclization reaction. The molar ratio of (R)-(4-chlorophenyl)(phenyl)methylamine to intermediate II was 1:1~3, and the weak base was DIPEA. Step 3: Intermediate III was reacted in a hydrochloric acid-methanol solution at 20-25℃ to obtain intermediate IV (R)-1-((4-chlorophenyl)(phenyl)methyl)piperazine; Step 4: Intermediate IV reacts with 2-chloroethanol under weakly alkaline conditions to generate intermediate V; Step 5: Intermediate V is dissolved in an organic solvent under alkaline conditions, and then reacted with sodium 2-chloroacetate to form a salt with hydrochloric acid to obtain levocetirizine hydrochloride; 。

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