Method for preparing citalopram bromate by applying dehydration membrane to reinforce etherification of 5-cyanodiol hydrochloride

Abstract

The invention discloses a method for preparing citalopram bromate by applying a dehydration membrane to enhance etherification of 5-cyanodiol hydrochloride, which comprises the following steps of: adding a raw material 5-cyanodiol hydrochloride, a solvent methylbenzene and a strong acid resin catalyst into a round-bottom reaction flask filled with a stirring magneton, arranging a water separation membrane in the reaction flask, the permeation side of the water separation membrane is kept at a high vacuum degree, and then heating reaction is performed on a magnetic stirring heater. In a toluene system, the water separation membrane performs in-situ removal on water generated by the reaction through steam permeation, so that the reaction is performed in a forward direction, thermodynamic equilibrium limitation is broken, the yield and purity of the product are improved, and coupling of the reaction and separation is realized. According to the invention, the strong acidic resin catalyst is coupled with the water separation membrane, the reaction steps are simple, and the reaction conditions are friendly; the catalyst is safe, stable, low in danger coefficient, green in catalysis, recyclable and easy to separate from reaction liquid; the water separation membrane can remove water in situ through steam permeation, and the raw material conversion rate and the product purity are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of citalopram bromate, and particularly relates to a method for preparing citalopram bromate by strengthening the etherification of 5-cyanodiol hydrochloride by using a dehydration membrane. Background Art

[0002] Citalopram Hydrobromide, chemical name is 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, hydrobromide, also known as Citalopram, is a potent and highly selective serotonin reuptake inhibitor (SSRI) developed by Lundbeck. It is clinically used to treat depressive disorders, and can also be used to treat social anxiety disorder, panic disorder, obsessive-compulsive disorder, Huntington's disease (HD) and premenstrual dysphoric disorder. Its traditional preparation method is to use concentrated sulfuric acid or concentrated phosphoric acid as a catalyst, but there are also some problems, such as: the cyano group of 5-cyanodiol hydrochloride will be hydrolyzed when catalyzed by concentrated sulfuric acid, and the risk factor is high when feeding; the other is to use p-toluenesulfonyl chloride / sodium hydroxide as a catalyst. Although the problem of cyano group hydrolysis of 5-cyanodiol hydrochloride is avoided, the reaction operation is complicated and the reaction needs to be carried out at -1℃~3℃, and the reaction conditions are harsh. Therefore, it is extremely important to develop a new, convenient and safe reaction system, which has important practical value. Summary of the invention

[0003] The traditional catalytic method of generating citalopram bromate by intramolecular dehydration and etherification of 5-cyanodiol hydrochloride has the problems of excessive waste acid, environmental pollution, high risk factor during feeding, harsh reaction conditions, etc. To solve these problems, the present invention provides a method for preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane. The present invention replaces the traditional catalyst with a strong acid resin catalyst, is green catalytic, can be recycled and reused, has simple reaction steps, and removes the byproduct water in situ by coupling the dehydration membrane, breaking the thermodynamic equilibrium limit, allowing the reaction to proceed in the forward direction, and improving the product yield and selectivity.

[0004] The specific technical solutions are as follows: A method for preparing citalopram bromate by using a dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride, comprising the following steps: 1) Preparation of steam permeation water separation membrane; 2) Adding the raw material 5-cyandiol hydrochloride, the strong acid resin catalyst and the solvent toluene into the reaction device in sequence; 3) The steam permeation water separation membrane assembly is placed in the reaction device, and the steam permeation water separation membrane assembly is connected to a vacuum pump to keep the permeation side of the steam permeation water separation membrane assembly in a vacuum state, and the air tightness is checked; 4) Turn on the vacuum pump and the magnetic stirring heater to stir and heat the raw materials in the reaction device; 5) After the reaction is completed, add an eluent to the solution after the reaction and perform heating and elution; 6) Filter to separate the strong acid resin catalyst from the mixed solution, separate the toluene solution from the eluent through a separatory funnel, and retain the toluene solution; 7) The toluene solution was subjected to rotary evaporation to obtain a light yellow oil, and then a solvent was added, followed by dropwise addition of hydrobromic acid, and the mixture was stirred for crystallization; 8) Filter, dry, collect the product, weigh and calculate the yield, and detect the product purity by HPLC.

[0005] Furthermore, the steam permeation water separation membrane in step 1) comprises a carrier and a supporting membrane material, wherein the carrier is a hollow alumina tube, a polyacrylonitrile tube, a polytetrafluoroethylene tube or a polyvinylidene fluoride tube; and the supporting membrane material is a PVA membrane, a PVA / GO mixed matrix membrane, a PVA / SiO 2 Mixed matrix membrane, PVA / Al 2 O 3 Mixed matrix membrane, PVA / molecular sieve mixed matrix membrane, PVA / COFs mixed matrix membrane, PVA / MOFs mixed matrix membrane or PVA / ILs mixed matrix membrane.

[0006] Furthermore, the strong acid resin catalyst in step 2) is HND-2, HND-583W, LX-50J, HND-260, LXC-101 or LXC-501.

[0007] Furthermore, the mass ratio of the raw material 5-cyandiol hydrochloride added in step 2) to the strong acid resin catalyst is 1:0.5~1:5, preferably 1:1~1:4; the molar ratio of the raw material 5-cyandiol hydrochloride added to the solvent toluene is 1:10~1:50, preferably 1:20~1:4.

[0008] Furthermore, in step 4), the reaction time is 1 h to 12 h, preferably 4 h to 8 h; the reaction temperature is 50° C. to 110° C., preferably 55° C. to 95° C.

[0009] Furthermore, in step 5), the eluent is 0.1~3 mol / L NaOH solution, 0.1~3 mol / L NaHCO 3 solution or 0.1~3mol / L HCl solution, preferably 1.5mol / L NaOH solution; the molar ratio of hydroxide ions or hydrogen ions of the eluent to the hydrogen ions of the strong acid resin catalyst is 1:1~3:1, preferably 2:1; the elution heating temperature is 25°C~65°C, preferably 45°C~55°C; the elution time is 0.5h~6h, preferably 0.8h~4h.

[0010] Furthermore, in step 7), the solvent is isopropanol or ethyl acetate, preferably ethyl acetate; after the hydrobromic acid is added dropwise, the pH is 1-5, preferably pH 2-4; and the stirring crystallization temperature is 10°C~30°C, preferably 21°C~26°C.

[0011] Furthermore, in step 8), the drying temperature is 40°C to 60°C, preferably 50°C to 55°C; the drying time is 4h to 8h, preferably 5h to 6h.

[0012] The beneficial effects of the present invention are: 1) Strong acid resin catalyst is used instead of traditional catalyst, which is green catalysis and environmentally friendly.

[0013] 2) Through the hydrophilic and screening properties of the dehydration membrane and the strong acid resin catalyst, reaction separation and coupling are achieved, the reaction process is enhanced, and higher conversion rate and selectivity are achieved.

[0014] 3) Through reaction separation and coupling, compared with the traditional reaction system, energy consumption is reduced, and product yield and purity are further improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 A schematic diagram of a reaction device for dehydration membrane-enhanced etherification of 5-cyanodiol hydrochloride to produce citalopram bromate; Figure 2 It is a comparison chart of the yield and purity of citalopram bromate produced by etherification of 5-cyanodiol hydrochloride with and without dehydration membrane enhancement; Figure 3 The figure is a comparison chart of the yield and purity of Comparative Example 3.

[0016] In the figure: 1. reaction flask; 2. steam permeation water separation membrane assembly; 3. three-head connecting pipe; 4. condenser; 5. buffer bottle; 6. vacuum pump. DETAILED DESCRIPTION

[0017] The present invention is further described below in conjunction with the examples and the accompanying drawings, but the protection scope 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.

[0018] Example 1: Preparation of dehydration membrane First, prepare a 5% polyvinyl alcohol (PVA) solution: weigh 10g of polyvinyl alcohol (1799 type) and dissolve it in 190g of deionized water, heat it in an oil bath at 90℃, and stir until it is completely dissolved. 2 O 3), in order to remove surface impurities, soak it in deionized water overnight, take it out and dry it at 80℃. After drying, it is baked at 500℃ in an air atmosphere for 4h. The baked hollow fiber carrier is fixed on the coating puller, the lower end of the carrier is sealed with raw tape, the coating puller is started, and the hollow fiber carrier is immersed in 5% PVA solution for 30s. After that, it is slowly lifted by the coating puller to ensure that the surface of the membrane is smooth, defect-free and of uniform thickness. It is dried at room temperature for 2min and then placed in an 80℃ oven for drying overnight. After drying, the PVA film is fixed on the coating puller again, and the above operation is repeated. The film is coated twice to obtain a hollow alumina tube loaded with PVA film as a steam permeation water separation membrane.

[0019] The following examples adopt Figure 1 The experimental device shown comprises a reaction flask (1), a steam permeation water separation membrane assembly (2), a three-head connecting pipe (3), a condenser (4), a buffer bottle (5) and a vacuum pump (6). The three-head connecting pipe (3) is arranged at the upper end of the reaction flask (1), the steam permeation water separation membrane assembly (2) is arranged in the reaction flask (1), the three-head connecting pipe (3) extends from the upper end of the steam permeation water separation membrane assembly (2), and is connected to the buffer bottle (5) through a pipeline and then connected to the vacuum pump (6), and the condenser (4) is arranged at an outlet of the three-head connecting pipe (3).

[0020] Example 2: Preparation of Citalopram Bromide by Coupling Dehydration Membrane with Strong Acid Resin Catalyst 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 3 g of HND-2, 20 mL (189 mM) of toluene, and a magnetic particle into a 100 mL round-bottom flask; 2) Build the experimental device, turn on the vacuum pump 6 to keep a high vacuum degree on the permeate side of the membrane, start stirring and heating, and carry out the reaction at a reaction temperature of 70°C and a reaction time of 4 hours; 3) After the reaction is completed, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and then heat and stir to elute. The elution temperature is 50°C and the elution time is 2 h; 4) After elution, filter to separate the mixed solution (toluene and sodium hydroxide solution) and the strong acid resin catalyst HND-2, then transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the 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 toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 77.3% and a purity of 97.5%.

[0021] Example 3: Preparation of Citalopram Bromide by Coupling Dehydration Membrane with Strong Acid Resin Catalyst 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 2 g of strong acid resin catalyst HND-2, 20 mL (189 mM) of toluene solvent into a 100 mL round-bottom flask, and then add a magnetic particle; 2) Build the experimental device, turn on the vacuum pump 6 to keep a high vacuum degree on the permeate side of the membrane, start stirring and heating, and carry out the reaction at a reaction temperature of 70°C and a reaction time of 4 hours; 3) After the reaction is completed, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and then heat and stir to elute. The elution temperature is 50°C and the elution time is 2 h; 4) After elution, filter to separate the mixed solution (toluene and sodium hydroxide solution) and the strong acid resin catalyst HND-2, then transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the 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 toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 70.5% and a purity of 96.4%.

[0022] Example 4: Preparation of Citalopram Bromide by Coupling Dehydration Membrane with Strong Acid Resin Catalyst 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 3 g of HND-2, 20 mL (189 mM) of toluene, and a magnetic particle into a 100 mL round-bottom flask; 2) Build the experimental device, turn on the vacuum pump 6 to keep a high vacuum degree on the permeate side of the membrane, start stirring and heating, and carry out the reaction at a reaction temperature of 80°C and a reaction time of 4 hours; 3) After the reaction is completed, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and then heat and stir to elute. The elution temperature is 50°C and the elution time is 2 h; 4) After elution, filter to separate the mixed solution (toluene and sodium hydroxide solution) and the strong acid resin catalyst HND-2, then transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the 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 toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 72.0% and a purity of 95.2%.

[0023] Example 5: Preparation of Citalopram Bromide by Coupling Dehydration Membrane with Strong Acid Resin Catalyst 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 3 g of HND-2, 20 mL (189 mM) of toluene, and a magnetic particle into a 100 mL round-bottom flask; 2) Build the experimental device, turn on the vacuum pump 6 to keep a high vacuum degree on the permeate side of the membrane, start stirring and heating, and carry out the reaction at a reaction temperature of 70°C and a reaction time of 3 hours; 3) After the reaction is completed, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and then heat and stir to elute. The elution temperature is 50°C and the elution time is 2 h; 4) After elution, filter to separate the mixed solution (toluene and sodium hydroxide solution) and the strong acid resin catalyst HND-2, then transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the 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 toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 69.7% and a purity of 96.7%.

[0024] Table 1 Summary of etherification of citalopram bromate under different reaction conditions

[0025] It can be found from the above table that the yield and purity after the reaction in Example 2 are the best, so the optimal reaction conditions are: the molar ratio of solvent to raw material is 35.8, the mass ratio of catalyst to raw material is 1.5, the reaction temperature is 70°C, and the reaction time is 4h.

[0026] Comparative Example 1: Preparation of Citalopram Bromide Using Strong Acidic Resin Catalyst 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 3 g of HND-2, 20 mL (189 mM) of toluene, and a magnetic particle into a 100 mL round-bottom flask; 2) Install the condenser, seal the system, start stirring and heating, and carry out condensation reflux reaction at a reaction temperature of 70°C and a reaction time of 4 hours; 3) After the reaction is completed, cool it to room temperature, add 20 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and then heat and stir to elute. The elution temperature is 50°C and the elution time is 2 h; 4) After elution, filter to separate the mixed solution (toluene and sodium hydroxide solution) and the strong acid resin catalyst HND-2, then transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the 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 toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 69.7% and a purity of 96.5%.

[0027] like Figure 2 As shown, by comparing Example 2 with Comparative Example 1, it is found that the yield and purity of the product obtained in Example 2 are higher than those of the product obtained in Comparative Example 1, which is attributed to the presence of the dehydration membrane. In the toluene reaction system, the dehydration membrane removes the water generated by the reaction in situ through steam permeation, breaking the thermodynamic equilibrium restriction and allowing the reaction to proceed in the forward direction. In the absence of a dehydration membrane, the water generated by the reaction in the toluene reaction system cannot be removed, which will inhibit the reaction from proceeding in the forward direction, and will also produce some side reactions, thereby affecting the product yield and purity.

[0028] Comparative Example 2: Preparation of Citalopram Bromide by Concentrated Phosphoric Acid Catalysis 1) Add 2 g (5.28 mM) of 5-cyanodiol hydrochloride, 20 mL (189 mM) of toluene, and a catalyst (6 g of 85% phosphoric acid + 1 g of deionized water) into a 100 mL round-bottom flask, and then add a magnetic particle; 2) Install the condenser, seal the system, start stirring and heating, and carry out condensation reflux reaction at a reaction temperature of 70°C and a reaction time of 5 hours; 3) After the reaction is completed, cool it to room temperature, add 40 mL of 1.5 mol / L NaOH solution into the round-bottom flask, and heat under reflux at 50°C with stirring for 2 h; 4) After the stirring reaction is completed, filter and transfer the mixed solution to a separatory funnel and let it stand for 1 hour; 5) After the separation is completed, discard the lower aqueous solution, take the upper toluene solution layer, and then perform rotary evaporation to remove the toluene to obtain a light yellow oily substance; 6) After the rotary evaporation is completed, add 20 mL of ethyl acetate to dissolve the light yellow oil. After it is completely dissolved, add a magnetic bar to stir it, and then slowly add 630 μL of 48% hydrobromic acid, pH=3, and stir at 25°C to crystallize. When a large amount of white crystals are seen to precipitate, add 20 mL of ethyl acetate and stir to crystallize for about 3 hours; 7) Afterwards, the mixture was filtered and the obtained crystals were vacuum dried at a temperature of 55°C for 6 hours; 8) The product Citalopram bromate was obtained with a yield of 67.5% and a purity of 97%.

[0029] like Figure 3 As shown, by comparing Example 2 with Example 2, it is found that the phosphoric acid catalyzes the generation of citalopram bromate, and the reaction time is relatively long, requiring 5 hours, the catalyst phosphoric acid dosage is large, requiring 6 g, and a large amount of sodium hydroxide 40 mL is required to neutralize the phosphoric acid, and the final yield of citalopram bromate is only 67.5%; while the membrane dehydration and strong acid resin catalytic coupling have a short reaction time of only 4 hours, and the amount of sodium hydroxide used for elution is also much less than the amount of sodium hydroxide used in the phosphoric acid catalytic process, requiring only 20 mL, and the final yield of citalopram bromate is as high as 77.3%, which further illustrates the advantages of the membrane dehydration and strong acid resin catalytic coupling.

[0030] In summary, the method of preparing citalopram bromate by etherification of 5-cyanodiol hydrochloride using a dehydration membrane is a new reaction method. By coupling the dehydration membrane with a strong acid resin catalyst, the reaction separation and in-situ water removal are achieved in the toluene system, breaking the thermodynamic equilibrium, allowing the reaction to proceed in the forward direction, and further improving the conversion rate and selectivity, which has great application value.

[0031] Obviously, the above embodiments are only examples for clear explanation, and are not intended to limit the implementation methods. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from them are still within the protection scope of the invention.

[0032] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being 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, characterized in that: The steps include: 1) Preparation of steam permeation water separation membrane; 2) Adding the raw material 5-cyandiol hydrochloride, the strong acid resin catalyst and the solvent toluene into the reaction device in sequence; 3) The steam permeation water separation membrane assembly is placed in the reaction device, and the steam permeation water separation membrane assembly is connected to a vacuum pump to keep the permeation side of the steam permeation water separation membrane assembly in a vacuum state, and the air tightness is checked; 4) Turn on the vacuum pump and the magnetic stirring heater to stir and heat the raw materials in the reaction device; 5) After the reaction is completed, add an eluent to the solution after the reaction and perform heating and elution; 6) Filter to separate the strong acid resin catalyst from the mixed solution, separate the toluene solution from the eluent through a separatory funnel, and retain the toluene solution; 7) Rotary evaporate the toluene solution to obtain a light yellow oil, add a solvent, then dropwise add hydrobromic acid, and stir to crystallize; 8) Filter, dry, collect the product, weigh and calculate the yield, and detect the product purity by HPLC.

2. A method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: The steam permeation water separation membrane described in step 1) includes a carrier and a supporting membrane material, wherein the carrier is a hollow alumina tube, a polyacrylonitrile tube, a polytetrafluoroethylene tube or a polyvinylidene fluoride tube; and the supporting 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.

3. A method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: The strong acid resin catalyst described in step 2) is HND-2, HND-583W, LX-50J, HND-260, LXC-101 or LXC-501.

4. A method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: The mass ratio of the raw material 5-cyandiol hydrochloride added in step 2) to the strong acid resin catalyst is 1:0.5~1:5, preferably 1:1~1:4; the molar ratio of the raw material 5-cyandiol hydrochloride added to the solvent toluene is 1:10~1:50, preferably 1:20~1:

4.

5. The method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: In step 4), the reaction time is 1 h to 12 h, preferably 4 h to 8 h; the reaction temperature is 50° C. to 110° C., preferably 55° C. to 95° C.

6. The method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: In step 5), the eluent is 0.1-3 mol / L NaOH solution, 0.1-3 mol / L NaHCO3 solution or 0.1-3 mol / L HCl solution, preferably 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°C-65°C, preferably 45°C-55°C; the elution time is 0.5h-6h, preferably 0.8h-4h.

7. The method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: In step 7), the solvent is isopropanol or ethyl acetate, preferably ethyl acetate; after adding hydrobromic acid dropwise, the pH is 1-5, preferably pH 2-4; the stirring crystallization temperature is 10°C~30°C, preferably 21°C~26°C.

8. The method for preparing citalopram bromate by using dehydration membrane to strengthen the etherification of 5-cyanodiol hydrochloride as claimed in claim 1, characterized in that: In step 8), the drying temperature is 40°C to 60°C, preferably 50°C to 55°C; the drying time is 4h to 8h, preferably 5h to 6h.

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