Process for the preparation of an intermediate of levocetirizine hydrochloride
By employing the reductive amination reaction of 4-chlorobenzophenone with anhydrous piperazine and the resolution method of L-di-p-methylbenzoyl tartaric acid, the problems of long preparation steps and low yield of levocetirizine hydrochloride intermediates have been solved, achieving an efficient and green production process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- FUAN PHARM GRP NINGBO TIANHENG PHARM CO LTD
- Filing Date
- 2026-03-25
- Publication Date
- 2026-07-24
AI Technical Summary
Existing methods for preparing levocetirizine hydrochloride intermediates suffer from lengthy steps, low yields, and a lack of environmental friendliness, especially with low yields during chiral resolution, leading to high production costs.
1-[(4-chlorophenyl)benzyl]piperazine was prepared by reductive amination of 4-chlorobenzophenone and anhydrous piperazine in the presence of a catalyst and hydrogen. Then, (R)-1-[(4-chlorophenyl)benzyl]piperazine was obtained by resolving it under alkaline conditions with L-di-p-methylbenzoyl tartaric acid as a resolving agent.
It achieves an efficient and green preparation route with high product yield, simplified process steps, reduced production costs, and is suitable for industrial production.
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Figure CN121914037B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of synthetic technology, and specifically to a method for preparing levocetirizine hydrochloride intermediates. Background Technology
[0002] Levocetirizine hydrochloride, chemically named 2-[2-[4-[(R)-(4-chlorophenyl)benzyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, was developed by UCB Pharma in Belgium and approved for marketing in the United States in 1995. It was first marketed in Germany on January 3, 2001, under the brand name Xyzal. Clinically, levocetirizine hydrochloride overcomes the common adverse reactions of racemic mixtures, such as sedation, drowsiness, gastrointestinal disturbances, and cardiovascular adverse reactions like arrhythmias. It requires a smaller dosage while exhibiting antihistamine activity comparable to cetirizine, making it a highly effective and long-lasting next-generation H1 receptor antagonist. It is primarily used to relieve allergic symptoms of allergic diseases, clinically treating allergic rhinitis, urticaria, angioedema, and other mucocutaneous allergic diseases, as well as allergic symptoms during colds. Common dosage forms include tablets and granules.
[0003] Currently, the mainstream route for levocetirizine hydrochloride reported in the literature mainly uses (R)-1-[(4-chlorophenyl)benzyl]piperazine as the key intermediate. The subsequent introduction of the ethoxyacetic acid side chain involves first N-alkylating 2-(2-chloroethoxy)acetic acid methyl ester or its equivalent with piperazine, and finally obtaining levocetirizine hydrochloride through a hydrolysis reaction.
[0004] The reported synthetic methods for the key intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine of levocetirizine hydrochloride are mainly divided into two categories:
[0005] The first type is the most mature method for industrial application. It involves first preparing the racemic 1-(4-chlorophenyl)-1-phenylmethylamine, then obtaining (R)-1-(4-chlorophenyl)-1-phenylmethylamine through chiral resolution, and finally cyclizing it with bis(2-chloroethyl)amine and its amino-protected derivative to obtain (R)-1-[(4-chlorophenyl)benzyl]piperazine. Reports of this type of method are as follows:
[0006] In 2008, Wang Qiyuan et al. reported a synthetic method for (R)-1-[(4-chlorophenyl)benzylmethyl]piperazine in the *Chinese Journal of Medicinal Chemistry*. This method uses chlorobenzene and benzoyl chloride as starting materials, first preparing 4-chlorobenzophenone, then obtaining 1-(4-chlorophenyl)-1-phenylmethylamine via the Leuckart-Wallach reaction, followed by chiral resolution with L-tartaric acid to obtain (R)-1-(4-chlorophenyl)-1-phenylmethylamine, and finally reacting it with bis(2-chloroethyl)amine hydrochloride and a ring to obtain (R)-1-[(4-chlorophenyl)benzylmethyl]piperazine. This route is lengthy, with low yields in the resolution step, resulting in significant pressure to control production costs. Furthermore, the final step uses unprotected bis(2-chloroethyl)amine, leading to numerous side reactions and further reducing the yield. The specific reaction route is as follows:
[0007]
[0008] WO2009062036A2 discloses a synthetic method for (R)-1-[(4-chlorophenyl)benzylmethyl]piperazine. This route involves an N-alkylation cyclization reaction of (R)-1-(4-chlorophenyl)-1-phenylmethylamine with N,N-bis(2-chloroethyl)-4-methoxybenzenesulfonamide in DIPEA at 125°C to yield the intermediate (R)-1-[(4-chlorophenyl)(phenyl)methyl]-4-[(4-methoxyphenyl)sulfonyl]piperazine. Finally, the sulfonyl protecting group is removed in hydrobromic acid and acetic acid at 70°C, followed by alkalization to obtain (R)-1-[(4-chlorophenyl)benzylmethyl]piperazine. This route requires the use of highly corrosive, irritating, and toxic hydrobromic acid during the deprotection process of the methoxybenzenesulfonyl group, making it less environmentally friendly and causing severe corrosion and damage to equipment. The specific reaction route is as follows:
[0009]
[0010] The second type of method involves first preparing the racemic 1-[(4-chlorophenyl)benzyl]piperazine, and then obtaining (R)-1-[(4-chlorophenyl)benzyl]piperazine by chiral resolution. This type of method is reported as follows:
[0011] US patent 20050227999 discloses a method for synthesizing 1-[(4-chlorophenyl)benzyl]piperazine. This route involves reacting 4-chlorobenzaldehyde with magnesium phenyl bromide to give 4-chlorodiphenylmethanol, which then reacts with thionyl chloride to give 4-diphenylchloromethane. Finally, it undergoes an N-alkylation reaction with piperazine under basic conditions to yield 1-[(4-chlorophenyl)benzyl]piperazine. This route uses Grignard reagents, posing significant safety risks in production. Furthermore, the final N-alkylation step has a very low yield, significantly increasing production costs and lacking commercial competitiveness. The specific reaction route is as follows:
[0012]
[0013] WO200978627A2 discloses a method for preparing (R)-1-[(4-chlorophenyl)benzyl]piperazine by chiral resolution of 1-[(4-chlorophenyl)benzyl]piperazine. This method uses N-acetyl-L-phenylalanine as a chiral resolving agent to obtain the target compound (R)-1-[(4-chlorophenyl)benzyl]piperazine in about 40% yield.
[0014] If the steps before resolution are long and the yield is low, then the cost advantage of this type of method is not as good as the first type of method. If the problem of green and efficient synthesis of 1-[(4-chlorophenyl)benzyl]piperazine can be solved, and then a chiral resolution method with high yield can be used, then this type of method will have a greater cost advantage in industrial applications. Summary of the Invention
[0015] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing levocetirizine hydrochloride intermediates, which addresses the shortcomings of the prior art.
[0016] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:
[0017] In a first aspect, the present invention discloses a method for preparing levocetirizine hydrochloride intermediate 1-[(4-chlorophenyl)benzyl]piperazine.
[0018] In some embodiments, the method includes the following steps: 4-chlorobenzophenone and anhydrous piperazine undergo a reductive amination reaction in an organic solvent containing a catalyst at a certain hydrogen pressure and temperature to obtain 1-[(4-chlorophenyl)benzyl]piperazine.
[0019] In some embodiments, the molar ratio of 4-chlorobenzophenone to anhydrous piperazine is 1:1-7, and in some embodiments it is 1:2-5.
[0020] In some embodiments, the catalyst for the reductive amination reaction is any one or a combination of Raney nickel, 5 wt% platinum carbon, and 10 wt% platinum carbon, with Raney nickel being used in some embodiments; the amount of catalyst added is 2.5%-15% of the mass of 4-chlorobenzophenone, such as 5%~10% or 12%.
[0021] In some embodiments, the organic solvent is an alcoholic organic solvent and / or tetrahydrofuran, wherein the alcoholic organic solvent is a C1-C5 alcoholic organic solvent in some embodiments, and ethanol and / or isopropanol in some embodiments; and the concentration of the 4-chlorobenzophenone is 0.08-0.18 g / mL in some embodiments, and 0.1-0.16 g / mL in some embodiments.
[0022] In some embodiments, the hydrogen pressure is 0.5-4 MPa, and in some embodiments it is 1.0-3.0 MPa.
[0023] In some embodiments, the reaction temperature is 90-160°C, and in some embodiments it is 100-150°C; the reaction time is 10-20 h.
[0024] In some embodiments, after the reaction is completed, the reaction system is cooled to room temperature, replaced with an inert gas, and then subjected to a first filtration. The resulting concentrate is then mixed with water and stirred, followed by a second filtration. The resulting filter cake is 1-[(4-chlorophenyl)benzyl]piperazine. In some embodiments, the inert gas is nitrogen. In some embodiments, 200-400 mL of solvent, such as 300 mL, is filtered out in the first filtration. In some embodiments, the volume of water added during the mixing process is 2-6 mL / g of the mass-to-volume ratio of 4-chlorobenzophenone, and in some embodiments, it is 4 mL / g. In some embodiments, the second stirring is performed at room temperature for 20-40 min, such as 30 min.
[0025] Secondly, this invention discloses a method for preparing the key intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine of levocetirizine hydrochloride. In some embodiments, the method involves resolving 1-[(4-chlorophenyl)benzyl]piperazine in an organic solvent using L-di-p-methylbenzoyl tartaric acid as a resolving agent, and then freeing it under alkaline conditions to obtain the key intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine of levocetirizine hydrochloride.
[0026] In some embodiments, the 1-[(4-chlorophenyl)benzyl]piperazine is prepared by the method described in the first aspect above, or by using existing technology. Specifically, in some embodiments, 4-chlorobenzophenone and anhydrous piperazine undergo a reductive amination reaction in an organic solvent containing a catalyst under a certain hydrogen pressure and temperature to obtain 1-[(4-chlorophenyl)benzyl]piperazine; the obtained 1-[(4-chlorophenyl)benzyl]piperazine is resolved in an organic solvent using L-di-p-methylbenzoyl tartaric acid as a resolving agent, and then released under alkaline conditions to obtain the key intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine of levocetirizine hydrochloride.
[0027] In some embodiments, the organic solvent used for the separation is an alcoholic organic solvent and / or tetrahydrofuran; the alcoholic organic solvent is any one of methanol, ethanol, and tetrahydrofuran, and in some embodiments it is ethanol; the volume-to-mass ratio of the organic solvent to 1-[(4-chlorophenyl)benzyl]piperazine is 6-15 mL / g, and in some embodiments it is 7-12 mL / g.
[0028] In some embodiments, the molar ratio of 1-[(4-chlorophenyl)benzyl]piperazine to L-di-p-methylbenzoyl tartaric acid is 1:0.2-1.5, and in some embodiments it is 1:0.5-1; in some embodiments, after adding L-di-p-methylbenzoyl tartaric acid to the reaction system, the temperature is lowered to crystallize, and in some embodiments the temperature is lowered to 0-10°C, and the crystallization time is 5-15 h; in some embodiments, the crystallization is carried out by stirring.
[0029] In some embodiments, after adding L-di-p-methylbenzoyl tartaric acid to the reaction system, the mixture is cooled to crystallize, filtered, and the resulting filter cake is then mixed with water and alkali. In some embodiments, the amount of water added is 8-12 times, such as 10 times, the mass of 1-[(4-chlorophenyl)benzyl]piperazine.
[0030] In some embodiments, the base used is any one or a combination of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, and in some embodiments it is sodium hydroxide; the molar ratio of 1-[(4-chlorophenyl)benzyl]piperazine to the base is 1:0.2-1, and in some embodiments it is 1:0.4-0.6.
[0031] In some embodiments, after adding alkali to the reaction system, the mixture is kept at a constant temperature and stirred, then filtered. The filtered cake is (R)-1-[(4-chlorophenyl)benzyl]piperazine. In some embodiments, the temperature for keeping the mixture at a constant temperature is 20~30°C, and the stirring time is 1~3 h.
[0032] The method provided by this invention solves the problems of long steps, low yield, and lack of environmental friendliness in the preparation of 1-[(4-chlorophenyl)benzyl]piperazine, as well as the low yield during chiral resolution. It provides an efficient and green preparation route with the advantages of inexpensive and readily available materials, short process steps, high product yield, low production cost, and environmental friendliness.
[0033] Beneficial effects:
[0034] The raw materials and auxiliary materials used in this invention are all readily available. Most importantly, this invention develops a novel, efficient, and green process route. The entire reaction route is short and easy to operate, and the yield of the product (R)-1-[(4-chlorophenyl)benzyl]piperazine is high, with an overall yield of up to 40% based on 4-chlorobenzophenone. In particular, this invention uses 4-chlorobenzophenone as a raw material to obtain 1-[(4-chlorophenyl)benzyl]piperazine in a one-step reaction with a yield as high as 84%-92%, which is conducive to realizing industrial production. Attached Figure Description
[0035] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.
[0036] Figure 1 This is a reaction route diagram for step (1) of each embodiment of the present invention.
[0037] Figure 2 This is a reaction route diagram for step (2) of each embodiment of the present invention.
[0038] Figure 3 The image shows the HRMS spectrum of 1-[(4-chlorophenyl)benzyl]piperazine obtained in Example 1 of this invention.
[0039] Figure 4 The 1-[(4-chlorophenyl)benzyl]piperazine obtained in Example 1 of this invention 1 H-NMR spectrum.
[0040] Figure 5 The chiral HPLC spectrum of (R)-1-[(4-chlorophenyl)benzyl]piperazine obtained in Example 1 of this invention is shown. Detailed Implementation
[0041] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.
[0042] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.
[0043] Example 1:
[0044] In this embodiment, the preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine is as follows:
[0045] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0046] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 99.4 g (1.15 mol) of anhydrous piperazine, 400 mL of ethanol, and 5 g of Raney nickel were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 3.0 MPa. The reaction was carried out at 140-150 °C for 20 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min and then filtered. The filter cake was dried under reduced pressure to obtain 60.9 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 92%.
[0047] HRMS spectrum as follows Figure 3As shown, HRMS (ESI) found 287.1312 [M+H]. + .
[0048] 1 H-NMR spectrum as shown Figure 4 As shown, 1 H NMR (400 MHz, CDCl3): δ = 7.365 – 7.338 (m, 4H), 7.284 – 7.158 (m, 5H), 4.189 (s, 1H), 2.875 (t, J = 4.8 Hz, 4H), 2.334 (s,4H), 1.568 (s, 1H).
[0049] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0050] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 350 mL of ethanol were added to a reaction vessel and stirred until dissolved. Then, 33.7 g (87.17 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred until dissolved. The mixture was then cooled to 0–10 °C and stirred to crystallize for 15 h. The crystals were filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred at 20–30 °C for 3 h. The crystals were then filtered again, and the filter cake was dried under reduced pressure to obtain 21.5 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 43%.
[0051] Chiral HPLC chromatogram as shown Figure 5 As shown, the ee value of (R)-1-[(4-chlorophenyl)benzyl]piperazine is 99.8252%.
[0052] Example 2:
[0053] The preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine in this embodiment is as follows:
[0054] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0055] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 39.8 g (461.54 mmol) of anhydrous piperazine, 400 mL of ethanol, and 5 g of Raney nickel were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 3.0 MPa. The reaction was carried out at 140-150 °C for 20 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min and then filtered. The filter cake was dried under reduced pressure to obtain 58.2 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 88%.
[0056] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0057] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 350 mL of ethanol were added to a reaction vessel and stirred until dissolved. Then, 67.4 g (174.34 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred until dissolved. The mixture was then cooled to 0–10 °C and stirred to crystallize for 15 h. The mixture was filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred at 20–30 °C for 3 h. The mixture was then filtered again, and the filter cake was dried under reduced pressure to obtain 18.5 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 37%.
[0058] Example 3:
[0059] The preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine in this embodiment is as follows:
[0060] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0061] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 99.4 g (1.15 mol) of anhydrous piperazine, 400 mL of ethanol, and 5 g of 5% platinum carbon were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 3.0 MPa. The reaction was carried out at 140-150 °C for 20 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min, then filtered. The filter cake was dried under reduced pressure to obtain 59.5 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 90%.
[0062] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0063] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 350 mL of ethanol were added to a reaction vessel and stirred until dissolved. Then, 33.7 g (87.17 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred until dissolved. The mixture was then cooled to 0–10 °C and stirred to crystallize for 5 h. The crystals were filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred at 20–30 °C for 3 h. The crystals were then filtered again, and the filter cake was dried under reduced pressure to obtain 17.5 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 35%.
[0064] Example 4:
[0065] The preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine in this embodiment is as follows:
[0066] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0067] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 99.4 g (1.15 mol) of anhydrous piperazine, 400 mL of ethanol, and 2.5 g of 10% platinum carbon were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 1.0 MPa. The reaction was carried out at 100-110 °C for 10 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min and then filtered. The filter cake was dried under reduced pressure to obtain 57.0 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 86%.
[0068] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0069] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 600 mL of ethanol were added to a reaction vessel and stirred until dissolved. Then, 33.7 g (87.17 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred until dissolved. The mixture was then cooled to 0–10 °C and stirred to crystallize for 15 h. The crystals were filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred at 20–30 °C for 3 h. The crystals were then filtered again, and the filter cake was dried under reduced pressure to obtain 19.5 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 39%.
[0070] Example 5:
[0071] The preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine in this embodiment is as follows:
[0072] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0073] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 99.4 g (1.15 mol) of anhydrous piperazine, 400 mL of ethanol, and 2.5 g of Raney nickel were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 3.0 MPa. The reaction was carried out at 140-150 °C for 20 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min and then filtered. The filter cake was dried under reduced pressure to obtain 59.6 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 90%.
[0074] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0075] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 350 mL of methanol were added to a reaction vessel and stirred until dissolved. Then, 33.7 g (87.17 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred until dissolved. The mixture was then cooled to 0–10 °C and stirred to crystallize for 15 h. The crystals were filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred at 20–30 °C for 3 h. The crystals were then filtered again, and the filter cake was dried under reduced pressure to obtain 14.0 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 28%.
[0076] Example 6:
[0077] The preparation method of (R)-1-[(4-chlorophenyl)benzyl]piperazine in this embodiment is as follows:
[0078] (1) Preparation of 1-[(4-chlorophenyl)benzyl]piperazine
[0079] At room temperature, 50.0 g (230.77 mmol) of 4-chlorobenzophenone, 99.4 g (1.15 mol) of anhydrous piperazine, 400 mL of isopropanol, and 5 g of Raney nickel were added to a high-pressure hydrogenation reactor. After the addition was complete, the system was purged with nitrogen and then hydrogen gas was introduced to a pressure of 3.0 MPa. The reaction was carried out at 140-150 °C for 20 h. The system was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated to yield approximately 300 mL of solvent. 200 mL of purified water was added to the concentrate, and the mixture was stirred at room temperature for 30 min and then filtered. The filter cake was dried under reduced pressure to obtain 55.6 g of 1-[(4-chlorophenyl)benzyl]piperazine, with a molar yield of 84%.
[0080] (2) Preparation of (R)-1-[(4-chlorophenyl)benzyl]piperazine
[0081] At room temperature, 50 g (174.34 mmol) of 1-[(4-chlorophenyl)benzyl]piperazine and 350 mL of tetrahydrofuran were added to a reaction vessel and stirred until dissolved. Then, 33.7 g (87.17 mmol) of L-di-p-methylbenzoyl tartaric acid was added, and the mixture was stirred and cooled to 0–10 °C for 15 h to crystallize. The mixture was filtered, and the filter cake was added to 500 mL of purified water. 3.5 g (87.17 mmol) of sodium hydroxide was added, and the mixture was stirred and kept at 20–30 °C for 3 h. The mixture was then filtered again, and the filter cake was dried under reduced pressure to obtain 20.0 g of (R)-1-[(4-chlorophenyl)benzyl]piperazine, with a yield of 40%.
[0082] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.
Claims
1. A method for preparing levocetirizine hydrochloride intermediate 1-[(4-chlorophenyl)benzyl]piperazine, characterized in that, include: 4-Chlorobenzophenone and anhydrous piperazine undergo a reductive amination reaction in an organic solvent containing a catalyst to yield 1-[(4-chlorophenyl)benzyl]piperazine; the molar ratio of 4-chlorobenzophenone to anhydrous piperazine is 1:2-5; the concentration of 4-chlorobenzophenone is 0.1-0.16 g / mL; the catalyst is any one or a combination of Raney nickel, 5 wt% platinum-carbon, and 10 wt% platinum-carbon; the amount of catalyst added is 2.5%-15% of the mass of 4-chlorobenzophenone; the reductive amination reaction is carried out in a hydrogen atmosphere; the pressure of the hydrogen is 1.0-3.0 MPa; and the temperature of the reductive amination reaction is 100-150℃.
2. The preparation method according to claim 1, characterized in that, The catalyst is added at a rate of 5%-10% of the mass of 4-chlorobenzophenone.
3. The preparation method according to claim 1, characterized in that, The organic solvent is an alcohol-based organic solvent and / or tetrahydrofuran.
4. A method for preparing the intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine, characterized in that, include: (1) 4-Chlorobenzophenone and anhydrous piperazine undergo a reductive amination reaction in an organic solvent containing a catalyst to give 1-[(4-chlorophenyl)benzyl]piperazine; (2) 1-[(4-chlorophenyl)benzyl]piperazine was resolved in an organic solvent using L-di-p-methylbenzoyl tartaric acid as a resolving agent, and then released under alkaline conditions to give the intermediate (R)-1-[(4-chlorophenyl)benzyl]piperazine of levocetirizine hydrochloride; In step (1), the molar ratio of 4-chlorobenzophenone to anhydrous piperazine is 1:2-5; the concentration of 4-chlorobenzophenone is 0.1-0.16 g / mL; the catalyst is any one or a combination of Raney nickel, 5 wt% platinum carbon, and 10 wt% platinum carbon; the amount of catalyst added is 2.5%-15% of the mass of 4-chlorobenzophenone; the reductive amination reaction is carried out in a hydrogen atmosphere; the pressure of the hydrogen is 1.0~3.0 MPa; and the temperature of the reductive amination reaction is 100~150℃.
5. The preparation method according to claim 4, characterized in that, In step (2), the volume-to-mass ratio of the organic solvent to 1-[(4-chlorophenyl)benzyl]piperazine is 6-15 mL / g, and the molar ratio of 1-[(4-chlorophenyl)benzyl]piperazine to L-di-p-methylbenzoyl tartaric acid is 1:0.2-1.
5.
6. The preparation method according to claim 4, characterized in that, In step (2), the volume-to-mass ratio of the organic solvent to 1-[(4-chlorophenyl)benzyl]piperazine is 7-12 mL / g, and the molar ratio of 1-[(4-chlorophenyl)benzyl]piperazine to L-di-p-methylbenzoyl tartaric acid is 1:0.5-1.
7. The preparation method according to claim 4, characterized in that, In step (2), the organic solvent is an alcoholic organic solvent and / or tetrahydrofuran; the base used in the alkaline conditions is any one or a combination of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate; the molar ratio of 1-[(4-chlorophenyl)benzyl]piperazine to the base is 1:0.2-1.
8. The preparation method according to claim 4, characterized in that, In step (2), L-di-p-methylbenzoyl tartaric acid is added to the reaction system and then cooled to 0-10℃ to crystallize; alkali is added to the reaction system and then kept warm and stirred; the temperature of the warming is 20~30℃.