A method for preparing citalopram bromide by etherification of 5-cyanodiol hydrochloride using a dehydration membrane
By using a strong acid resin catalyst and dehydration membrane technology, the problems of waste acid pollution and harsh reaction conditions in the preparation of citalopram bromate were solved, achieving a highly efficient and environmentally friendly preparation process and improving product yield and purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHEJIANG UNIV OF TECH
- Filing Date
- 2025-02-28
- Publication Date
- 2026-06-19
AI Technical Summary
Existing methods for preparing citalopram bromate suffer from serious waste acid pollution, harsh reaction conditions, and high risk factors. Furthermore, traditional catalysts are complex to operate and have low reaction efficiency.
By replacing traditional catalysts with strong acid resin catalysts and combining them with dehydration membrane technology, water byproducts is removed in situ through steam permeation water separation membranes, breaking the thermodynamic equilibrium, achieving reaction separation and coupling, and improving conversion rate and selectivity.
It achieves green catalysis, simplifies operation, reduces energy consumption, improves the yield and purity of citalopram bromate, and reduces environmental pollution.
Smart Images
Figure CN120097946B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of citalopram bromate preparation technology, specifically relating to a method for preparing citalopram bromate by using a dehydration membrane to enhance the etherification of 5-cyanodiol hydrochloride. Background Technology
[0002] Citalopram hydrobromide, chemically known as 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-onitrile, is a hydrobromide, also called Citalopram. Developed by Lundbeck, it is a potent and highly selective serotonin reuptake inhibitor (SSRI) used clinically to treat depressive disorders, as well as social anxiety disorder, panic disorder, obsessive-compulsive disorder, Huntington's disease (HD), and premenstrual syndrome. Traditional preparation methods include one using concentrated sulfuric acid or concentrated phosphoric acid as a catalyst, but this has several drawbacks, such as the hydrolysis of the cyano group in 5-cyanodiol hydrochloride during concentrated sulfuric acid catalysis, resulting in a high risk of adverse reactions. Another method uses p-toluenesulfonyl chloride / sodium hydroxide as a catalyst, which avoids the hydrolysis of the cyano group in 5-cyanodiol hydrochloride, but this method is complex and requires harsh conditions, needing to be carried out at -1°C to 3°C. Therefore, developing a new, convenient, and safe reaction system is extremely important and has significant practical value. Summary of the Invention
[0003] Traditional catalytic methods for the intramolecular dehydration etherification of 5-cyanodiol hydrochloride to citalopram bromate suffer from problems such as excessive waste acid, environmental pollution, high risk during feed, and harsh reaction conditions. To address these issues, this invention provides a method for preparing citalopram bromate by enhancing the etherification of 5-cyanodiol hydrochloride using a dehydration membrane. This invention replaces the traditional catalyst with a strong acid resin catalyst, achieving green catalysis that is recyclable and simple in reaction steps. Simultaneously, the coupled dehydration membrane removes the byproduct water in situ, breaking the thermodynamic equilibrium constraint and driving the reaction forward, thereby improving product yield and selectivity.
[0004] The specific technical solution is as follows:
[0005] A method for preparing citalopram bromate by enhancing the etherification of 5-cyanodiol hydrochloride using a dehydration membrane includes the following steps:
[0006] 1) Preparation of vapor permeate water separation membrane;
[0007] 2) Add the raw material 5-cyanodiol hydrochloride, the strong acid resin catalyst, and the solvent toluene to the reaction apparatus in sequence;
[0008] 3) Place the vapor permeate water separation membrane module inside the reaction device, connect the vapor permeate water separation membrane module to the vacuum pump, keep the permeate side of the vapor permeate water separation membrane module under vacuum, and check the airtightness;
[0009] 4) Turn on the vacuum pump and the magnetic stirrer heater to stir and heat the raw materials in the reaction apparatus.
[0010] 5) After the reaction is complete, add the eluent to the solution and heat to elute;
[0011] 6) Filtration: Separate the strong acid resin catalyst from the mixture by separating the toluene solution from the eluent using a separatory funnel, and retain the toluene solution.
[0012] 7) The toluene solution was rotary evaporated to obtain a pale yellow oily substance. Solvent was then added, followed by the dropwise addition of hydrobromic acid, and the mixture was stirred to induce crystallization.
[0013] 8) Filter, dry, collect the product, weigh it, calculate the yield, and detect the product purity by HPLC.
[0014] Further, the vapor permeate water separation membrane described in step 1) includes a carrier and a loaded membrane material. The carrier is a hollow alumina tube, a polyacrylonitrile tube, a polytetrafluoroethylene tube, or a polyvinylidene fluoride tube. The loaded membrane material is a PVA membrane, a PVA / GO mixed matrix membrane, a PVA / SiO2 mixed matrix membrane, a PVA / Al2O3 mixed matrix membrane, a PVA / molecular sieve mixed matrix membrane, a PVA / COFs mixed matrix membrane, a PVA / MOFs mixed matrix membrane, or a PVA / ILs mixed matrix membrane.
[0015] Further, the strong acid resin catalyst mentioned in step 2) is HND-2, HND-583W, LX-50J, HND-260, LXC-101 or LXC-501.
[0016] Further, in step 2), the mass ratio of the added raw material 5-cyanodiol hydrochloride to the strong acid resin catalyst is 1:0.5 to 1:5, preferably 1:1 to 1:4; the molar ratio of the added raw material 5-cyanodiol hydrochloride to the solvent toluene is 1:10 to 1:50, preferably 1:20 to 1:40.
[0017] Furthermore, in step 4), the reaction time is 1h to 12h, preferably 4h to 8h; the reaction temperature is 50℃ to 110℃, preferably 55℃ to 95℃.
[0018] Further, in step 5), the eluent is a 0.1~3 mol / L NaOH solution, a 0.1~3 mol / L NaHCO3 solution, or a 0.1~3 mol / L HCl solution, preferably a 1.5 mol / L NaOH solution; the molar ratio of hydroxide ions or hydrogen ions in the eluent to hydrogen ions in the strong acid resin catalyst is 1:1~3:1, preferably 2:1; the elution heating temperature is 25℃~65℃, preferably 45℃~55℃; and the elution time is 0.5h~6h, preferably 0.8h~4h.
[0019] Further, in step 7), the solvent is isopropanol or ethyl acetate, preferably ethyl acetate; after adding hydrobromic acid, the pH is 1-5, preferably pH 2-4; the stirring crystallization temperature is 10℃~30℃, preferably 21℃~26℃.
[0020] Furthermore, in step 8), the drying temperature is 40℃~60℃, preferably 50℃~55℃; the drying time is 4h~8h, preferably 5h~6h.
[0021] The beneficial effects of this invention are as follows:
[0022] 1) Strong acid resin catalysts are used instead of traditional catalysts, which is green catalysis and environmentally friendly.
[0023] 2) By utilizing the hydrophilic and sieving properties of the dehydration membrane, as well as the strong acid resin catalyst, reaction separation and coupling are achieved, the reaction process is enhanced, and higher conversion rate and selectivity are achieved.
[0024] 3) By separating and coupling reactions, energy consumption is reduced and product yield and purity are further improved compared with traditional reaction systems. Attached Figure Description
[0025] Figure 1 A schematic diagram of the apparatus used for the dehydration membrane-enhanced etherification of 5-cyanodiol hydrochloride to produce citalopram bromic acid;
[0026] Figure 2 A comparison chart showing the yield and purity of citalopram bromate produced by the etherification of 5-cyanodiol hydrochloride with and without a dehydration membrane enhancement.
[0027] Figure 3 This is a comparison chart of the yield and purity of Example 3.
[0028] In the diagram: 1. Reaction flask; 2. Vapor permeate water separation membrane assembly; 3. Three-way connecting pipe; 4. Condenser; 5. Buffer bottle; 6. Vacuum pump. Detailed Implementation
[0029] The present invention will be further described below with reference to the embodiments and accompanying drawings, but the scope of protection of the present invention is not limited thereto. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be purchased from chemical companies.
[0030] Example 1: Preparation of dehydration membrane
[0031] First, prepare a 5% polyvinyl alcohol (PVA) solution: Weigh 10g of polyvinyl alcohol (type 1799) and dissolve it in 190g of deionized water. Heat in an oil bath at 90℃ and stir until completely dissolved. Next, cut a certain length of four-channel hollow alumina carrier (α-Al2O3). To remove surface impurities, soak it in deionized water overnight, then remove and dry at 80℃. After drying, calcine it in an air atmosphere at 500℃ for 4 hours. Fix the calcined hollow fiber carrier onto a coating lifting machine, sealing the lower end of the carrier with PTFE tape. Start the coating lifting machine and immerse the hollow fiber carrier in the 5% PVA solution for 30 seconds. Then, slowly lift it through the coating lifting machine to ensure a smooth, defect-free film surface and uniform thickness. Dry at room temperature for 2 minutes, then place it in an 80℃ oven to dry overnight. After drying, the PVA membrane is fixed on the coating lifting machine again, and the above operation is repeated. The coating is done twice to obtain a hollow alumina tube loaded with PVA membrane as a vapor permeation water separation membrane.
[0032] The following embodiments employ the following methods: Figure 1 The experimental setup shown includes a reaction flask (1), a vapor permeation water separation membrane assembly (2), a three-way connector (3), a condenser (4), a buffer bottle (5), and a vacuum pump (6). The three-way connector (3) is located at the upper end of the reaction flask (1). The vapor permeation water separation membrane assembly (2) is located inside the reaction flask (1). The three-way connector (3) extends from the upper end of the vapor permeation water separation membrane assembly (2) and is connected to the buffer bottle (5) and then to the vacuum pump (6) via a pipeline. The condenser (4) is located at one outlet of the three-way connector (3).
[0033] Example 2: Enhanced preparation of citalopram bromate by coupling dehydration membrane with a strong acid resin catalyst
[0034] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 3g (3g) of strong acid resin catalyst HND-2, and 20mL (189mM) of toluene solvent to a 100mL round-bottom flask, and then add a magnetic flask;
[0035] 2) Set up the experimental setup, turn on vacuum pump 6 to maintain a high vacuum on the permeation side of the membrane, turn on stirring and heating to carry out the reaction at a temperature of 70℃ for 4 hours.
[0036] 3) After the reaction is complete, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution to the round-bottom flask, and then heat and stir to elute. The elution temperature is 50℃ and the elution time is 2 h.
[0037] 4) After elution, filter the mixture (toluene and sodium hydroxide solution) to separate it from the strong acid resin catalyst HND-2. Then transfer the mixture to a separatory funnel and let it stand for 1 hour.
[0038] 5) After the liquid-liquid separation is completed, discard the lower layer of sodium hydroxide solution, take the upper layer of toluene solution, and then perform rotary evaporation to remove the toluene, resulting in a pale yellow oily substance.
[0039] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0040] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0041] 8) The product citalopram bromate was obtained with a yield of 77.3% and a purity of 97.5%.
[0042] Example 3: Enhanced preparation of citalopram bromate by coupling dehydration membrane with a strong acid resin catalyst
[0043] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 2g (2g) of strong acid resin catalyst HND-2, and 20mL (189mM) of toluene solvent to a 100mL round-bottom flask, and then add a magnetic flask;
[0044] 2) Set up the experimental setup, turn on vacuum pump 6 to maintain a high vacuum on the permeation side of the membrane, turn on stirring and heating to carry out the reaction at a temperature of 70℃ for 4 hours.
[0045] 3) After the reaction is complete, allow it to cool to room temperature. Add 20 mL of 1.5 mol / L NaOH solution to the round-bottom flask, and then heat and stir to elute. The elution temperature is 50℃, and the elution time is 2 h.
[0046] 4) After elution, filter the mixture (toluene and sodium hydroxide solution) to separate it from the strong acid resin catalyst HND-2. Then transfer the mixture to a separatory funnel and let it stand for 1 hour.
[0047] 5) After the liquid-liquid separation is completed, discard the lower layer of sodium hydroxide solution, take the upper layer of toluene solution, and then perform rotary evaporation to remove the toluene, resulting in a pale yellow oily substance.
[0048] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0049] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0050] 8) Citalopram bromate was obtained with a yield of 70.5% and a purity of 96.4%.
[0051] Example 4: Enhanced preparation of citalopram bromate by coupling dehydration membrane with strong acid resin catalyst
[0052] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 3g (3g) of strong acid resin catalyst HND-2, and 20mL (189mM) of toluene solvent to a 100mL round-bottom flask, and then add a magnetic flask.
[0053] 2) Set up the experimental setup, turn on vacuum pump 6 to maintain a high vacuum on the permeation side of the membrane, turn on stirring and heating to carry out the reaction at a temperature of 80℃ for 4 hours.
[0054] 3) After the reaction is complete, allow it to cool to room temperature. Add 20 mL of 1.5 mol / L NaOH solution to the round-bottom flask, and then heat and stir to elute. The elution temperature is 50℃, and the elution time is 2 h.
[0055] 4) After elution, filter the mixture (toluene and sodium hydroxide solution) to separate it from the strong acid resin catalyst HND-2. Then transfer the mixture to a separatory funnel and let it stand for 1 hour.
[0056] 5) After the liquid-liquid separation is completed, discard the lower layer of sodium hydroxide solution, take the upper layer of toluene solution, and then perform rotary evaporation to remove the toluene, resulting in a pale yellow oily substance.
[0057] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0058] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0059] 8) Citalopram bromate was obtained with a yield of 72.0% and a purity of 95.2%.
[0060] Example 5: Enhanced preparation of citalopram bromate by coupling dehydration membrane with strong acid resin catalyst
[0061] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 3g (3g) of strong acid resin catalyst HND-2, and 20mL (189mM) of toluene solvent to a 100mL round-bottom flask, and then add a magnetic flask.
[0062] 2) Set up the experimental setup, turn on vacuum pump 6 to maintain a high vacuum on the permeation side of the membrane, turn on stirring and heating to carry out the reaction at a temperature of 70℃ for 3 hours.
[0063] 3) After the reaction is complete, allow it to cool to room temperature. Add 20 mL of 1.5 mol / L NaOH solution to the round-bottom flask, and then heat and stir to elute. The elution temperature is 50℃, and the elution time is 2 h.
[0064] 4) After elution, filter the mixture (toluene and sodium hydroxide solution) to separate it from the strong acid resin catalyst HND-2. Then transfer the mixture to a separatory funnel and let it stand for 1 hour.
[0065] 5) After the liquid-liquid separation is completed, discard the lower layer of sodium hydroxide solution, take the upper layer of toluene solution, and then perform rotary evaporation to remove the toluene, resulting in a pale yellow oily substance.
[0066] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0067] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0068] 8) Citalopram bromate was obtained with a yield of 69.7% and a purity of 96.7%.
[0069] Table 1. Summary of Citalopram Bromate Formation under Different Reaction Conditions
[0070]
[0071] As can be seen from the table above, the yield and purity after the reaction in Example 2 were the best. Therefore, the optimal reaction conditions are: a solvent to raw material molar ratio of 35.8, a catalyst to raw material mass ratio of 1.5, a reaction temperature of 70°C, and a reaction time of 4 hours.
[0072] Comparative Example 1: Preparation of Citalopram Bromate using a Strong Acid Resin Catalyst
[0073] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 3g (3g) of strong acid resin catalyst HND-2, and 20mL (189mM) of toluene solvent to a 100mL round-bottom flask, and then add a magnetic flask.
[0074] 2) Install the condenser, seal the system, turn on the stirring and heating, and carry out the condensation reflux reaction at a reaction temperature of 70℃ for 4 hours;
[0075] 3) After the reaction is complete, allow it to cool to room temperature. Add 20 mL of 1.5 mol / L NaOH solution to the round-bottom flask, and then heat and stir to elute. The elution temperature is 50℃, and the elution time is 2 h.
[0076] 4) After elution, filter the mixture (toluene and sodium hydroxide solution) to separate it from the strong acid resin catalyst HND-2. Then transfer the mixture to a separatory funnel and let it stand for 1 hour.
[0077] 5) After the liquid-liquid separation is completed, discard the lower layer of sodium hydroxide solution, take the upper layer of toluene solution, and then perform rotary evaporation to remove the toluene, resulting in a pale yellow oily substance.
[0078] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0079] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0080] 8) Citalopram bromate was obtained with a yield of 69.7% and a purity of 96.5%.
[0081] like Figure 2As shown, a comparison between Example 2 and Comparative Example 1 reveals that the product yield and purity obtained in Example 2 are higher than those obtained in Comparative Example 1. This is attributed to the presence of the dehydration membrane. In the toluene reaction system, the dehydration membrane removes the water generated in the reaction in situ through vapor permeation, breaking the thermodynamic equilibrium and allowing the reaction to proceed in the forward direction. Without the dehydration membrane, the water generated in the toluene reaction system cannot be removed, which inhibits the forward reaction and also produces some side reactions, thus affecting the product yield and purity.
[0082] Comparative Example 2: Preparation of Citalopram Bromate by Concentrated Phosphoric Acid Catalysis
[0083] 1) Add 2g (5.28mM) of 5-cyanodiol hydrochloride, 20mL (189mM) of toluene solvent, and catalyst (6g of 85% phosphoric acid + 1g of deionized water) to a 100mL round-bottom flask, and then add a magnetic stir bar;
[0084] 2) Install the condenser, seal the system, turn on the stirrer and heat, and carry out the condensation reflux reaction at a temperature of 70°C for 5 hours.
[0085] 3) After the reaction is complete, allow it to cool to room temperature, add 40 mL of 1.5 mol / L NaOH solution to a round-bottom flask, and heat under reflux at 50°C for 2 hours with stirring.
[0086] 4) After the stirring reaction is complete, filter the mixture and transfer it to a separatory funnel. Let it stand for 1 hour to separate the liquids.
[0087] 5) After the liquid-liquid separation is completed, discard the lower aqueous layer, take the upper toluene solution layer, and then perform rotary evaporation to remove the toluene, obtaining a pale yellow oily substance.
[0088] 6) After rotary evaporation, add 20 mL of ethyl acetate and shake to dissolve the pale yellow oily substance. After it is completely dissolved, add a magnetic stir bar to stir it. Then slowly add 630 μL of 48% hydrobromic acid (pH=3) and stir at 25°C to induce crystallization. When a large amount of white crystals are observed to precipitate, add another 20 mL of ethyl acetate and stir to induce crystallization for about 3 hours.
[0089] 7) Afterwards, the crystals are filtered and then vacuum dried at 55°C for 6 hours.
[0090] 8) Citalopram bromate was obtained with a yield of 67.5% and a purity of 97%.
[0091] like Figure 3As shown, a comparison between Example 2 and Example 2 reveals that the phosphoric acid-catalyzed production of citalopram bromate requires a long reaction time of 5 hours, a large amount of phosphoric acid (6g), and a large amount of sodium hydroxide (40mL) is needed to neutralize the phosphoric acid, while the final yield of citalopram bromate is only 67.5%. In contrast, the membrane dehydration coupled with strong acid resin catalysis has a short reaction time of only 4 hours, requires far less sodium hydroxide (only 20mL) than the phosphoric acid-catalyzed process, and achieves a final citalopram bromate yield as high as 77.3%, further demonstrating the advantages of the membrane dehydration coupled with strong acid resin catalysis.
[0092] In summary, the method of preparing citalopram bromate by strengthening the etherification of 5-cyanodiol hydrochloride using a dehydration membrane is a novel reaction method. By coupling the dehydration membrane with a strong acid resin catalyst, in-situ dehydration is achieved in the toluene system, breaking the thermodynamic equilibrium and driving the reaction in the forward direction, thereby further improving the conversion rate and selectivity. This method has great application value.
[0093] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
[0094] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.
Claims
1. A method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane enhancement method, characterized in that, Includes the following steps: 1) Preparation of vapor permeate water separation membrane; 2) Add the raw material 5-cyanodiol hydrochloride, the strong acid resin catalyst, and the solvent toluene to the reaction apparatus in sequence; 3) Place the vapor permeate water separation membrane module inside the reaction device, connect the vapor permeate water separation membrane module to the vacuum pump, keep the permeate side of the vapor permeate water separation membrane module under vacuum, and check the airtightness; 4) Turn on the vacuum pump and the magnetic stirrer heater to stir and heat the raw materials in the reaction apparatus. 5) After the reaction is complete, add the eluent to the solution and heat to elute; 6) Filtration: Separate the strong acid resin catalyst from the mixture by separating the toluene solution from the eluent using a separatory funnel, and retain the toluene solution. 7) The toluene solution was rotary evaporated to obtain a pale yellow oily substance. Solvent was then added, followed by the dropwise addition of hydrobromic acid, and the mixture was stirred to induce crystallization. 8) Filter, dry, collect the product, weigh it, calculate the yield, and detect the product purity by HPLC; Step 1) The vapor permeate water separation membrane includes a carrier and a supported membrane material. The carrier is a hollow alumina tube, and the supported membrane material is a PVA membrane. The strong acid resin catalyst mentioned in step 2) is HND-2.
2. The method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane as described in claim 1, characterized in that, In step 2), the mass ratio of the added raw material 5-cyanodiol hydrochloride to the strong acid resin catalyst is 1:0.5 to 1:5; the molar ratio of the added raw material 5-cyanodiol hydrochloride to the solvent toluene is 1:10 to 1:
50.
3. The method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane as described in claim 1, characterized in that, In step 4), the reaction time is 1h to 12h and the reaction temperature is 50℃ to 110℃.
4. The method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane as described in claim 1, characterized in that, In step 5), the eluent is a 0.1-3 mol / L NaOH solution, a 0.1-3 mol / L NaHCO3 solution, or a 0.1-3 mol / L HCl solution; the molar ratio of hydroxide ions or hydrogen ions in the eluent to hydrogen ions in the strong acid resin catalyst is 1:1 to 3:1; the elution heating temperature is 25℃ to 65℃; and the elution time is 0.5h to 6h.
5. The method for preparing citalopram bromate by strengthening the etherification of 5-cyanodiol hydrochloride using a dehydration membrane as described in claim 1, characterized in that, In step 7), the solvent is isopropanol or ethyl acetate; after adding hydrobromic acid, the pH is 1-5; the stirring crystallization temperature is 10℃~30℃.
6. The method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane as described in claim 1, characterized in that, In step 8), the drying temperature is 40℃~60℃; the drying time is 4h~8h.