A method for preparing a high purity escitalopram s-diol intermediate

Abstract

The application belongs to the technical field of drug synthesis, and more particularly relates to a preparation method of a high-purity citalopram S-diol intermediate. The preparation method comprises the following steps: generating a racemic citalopram diol intermediate; adding an acid to quench the racemic citalopram diol intermediate, centrifuging, and concentrating the evaporation substrate by evaporation under reduced pressure to obtain an evaporation substrate; mixing the evaporation substrate with a mixed solvent, adding a chiral resolving agent, and performing chiral resolution; after the reaction is completed, cooling, incubation crystallization, washing and drying are performed to obtain the citalopram S-diol intermediate. Through optimization of the chiral resolution process, the racemic citalopram diol intermediate can be directly subjected to chiral resolution after simple post-treatment, and high-purity and high-optical-purity compound 1b can be directly prepared; meanwhile, a plurality of recrystallization processes can be omitted, the operation is simple, the production efficiency is high, and the cost is low.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis, and more specifically, relates to a method for preparing a high-purity citalopram S-diol intermediate. Background Technology

[0002] Escitalopram oxalate is one of the best-selling antidepressants worldwide since the 1990s. The S-diol intermediate of citalopram (compound 1b) is the core intermediate for the preparation of citalopram. The S-diol intermediate of citalopram is usually obtained by a series of complex processes from the racemic diol of the precursor (compound 1a) to obtain high-purity compound 1b.

[0003] .

[0004] To obtain high-purity compound 1b, the core technical bottleneck lies in the post-purification treatment of precursor compound 1a. It is generally believed in the industry that compound 1a must undergo complex post-purification treatment to prepare high-purity compound 1b, thereby meeting the requirements of the Japanese Pharmacopoeia (compound 1b purity ≥ 98%, optical purity enantiomers ≤ 0.1%).

[0005] The literature “Streamlined Atom-Economical Synthesis of Escitalopram: KilogramScale Process Optimization and Industrial-Scale Implementation”, Yang Peng, Organic Process Research & Development, DOI:10.1021 / acs.oprd.5c00188, presents the simplest process route for preparing high-purity compound 1b from compound 1a. The specific steps are as follows: after obtaining compound 1a from the reaction, the mixture undergoes quenching, extraction and separation, concentration, solvent dissolution, recrystallization with free alkali, and centrifugal drying to obtain a chirally resolvable substrate of compound 1a. Subsequently, compound 1a undergoes chiral resolution. The crude compound 1b obtained after chiral resolution does not meet the requirements of the Japanese Pharmacopoeia and requires further dissolution and ethanol recrystallization purification to achieve high purity and high optical purity. However, the above method still has the following problems: (1) It still requires multiple purification and crystallization operations, which are cumbersome, labor, energy consumption and material costs are high, and production efficiency is low. Specifically, the compound 1a obtained by the reaction needs to be dissolved in a solvent and recrystallized with free base before it can be chirally separated. The crude compound 1b obtained after chiral separation is still difficult to meet the actual needs and needs to be further recrystallized with ethanol to meet the needs. (2) The chiral separation process is difficult to control the isomers. The compound 1b obtained after chiral separation cannot directly meet the pharmacopoeia requirements and must be purified by recrystallization with ethanol.

[0006] Therefore, optimizing existing preparation methods to provide a simple, non-recrystallization method for preparing citalopram S-diol intermediates with high purity and optical purity has become an urgent technical problem to be solved. Summary of the Invention

[0007] To address the aforementioned problems in the existing technology, the primary objective of this invention is to provide a method for preparing a high-purity citalopram S-diol intermediate. By optimizing the chiral resolution process, compound 1a can be directly used for chiral resolution after simple post-treatment, directly preparing compound 1b with high purity and high optical purity. Simultaneously, the recrystallization of free base from compound 1a and the recrystallization purification process of crude compound 1b can be omitted, resulting in simple operation, high production efficiency, and low cost.

[0008] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention claims protection for a method for preparing a citalopram S-diol intermediate, comprising the following steps: S1. Under a nitrogen atmosphere, 5-cyanophthalide, BFB-Mg, CPA-Mg and toluene react to produce racemic citalopram diol intermediate 1a; S2. Post-treatment: The reaction was terminated by adding acid to the racemic citalopram diol intermediate, centrifuged to obtain the filtrate, and the filtrate was evaporated under reduced pressure at 70-80℃ to obtain an evaporated substrate with ≤3% toluene residue; S3. Chiral resolution and purification: Evaporate the substrate and mix with the mixed solvent, add the chiral resolving agent, and carry out chiral resolution at 35-45℃; after the reaction is completed, cool to 10-15℃, keep warm to crystallize, wash and dry to obtain the citalopram S-diol intermediate; In step S1, the reaction formula is as follows: ; In step S3, the mixed solvent is a mixture of anhydrous ethanol and 1,4-dioxane, and the volume percentage of 1,4-dioxane in the mixed solvent is 13-18%. The structural formula of the citalopram S-diol intermediate is: .

[0009] This invention optimizes the chiral resolution reaction, discovering that using a mixed solvent of anhydrous ethanol and 1,4-dioxane, and controlling the volume percentage of 1,4-dioxane in the mixed solvent, significantly improves the yield and optical purity of the chiral resolution product. Furthermore, under this premise, the inventors optimize the process conditions during chiral resolution, controlling the reaction temperature, etc. Through precise combined regulation of the above parameters, effective separation of impurities can be achieved, effectively improving the purity and optical purity of compound 1b.

[0010] The inventors unexpectedly discovered that by using a mixed solvent with a specific composition and optimizing the chiral resolution process conditions, the post-processing of compound 1a and the purification process of compound 1b after chiral resolution were significantly affected: (1) after the reaction, compound 1a only needs to undergo three simple post-processing operations of quenching-centrifugation-reduced pressure concentration to obtain crude compound 1a that can undergo subsequent chiral resolution reactions, without the need for purification operations such as extraction, solvent dissolution, and recrystallization of free base, which greatly reduces the post-processing operations of compound 1a; (2) after chiral resolution, compound 1b can be directly crystallized in one step to obtain a product that meets the Japanese Pharmacopoeia standard (purity of compound 1b ≥ 98%, optical purity enantiomers ≤ 0.1%), without the need for any further recrystallization purification operations. This invention simplifies the post-processing of compound 1a before chiral resolution and the purification process of compound 1b after chiral resolution by optimizing the chiral resolution reaction. The overall method is simple to operate, has high production efficiency, and low cost.

[0011] Furthermore, in step S2, the filtrate needs to be evaporated under reduced pressure at 70-80°C to obtain an evaporated substrate with ≤3% toluene residue. When the toluene residue in the evaporated substrate exceeds 3%, it will greatly affect the subsequent resolution reaction of compound 1b. The resolved compound 1b has low optical purity and requires an additional recrystallization purification step. Furthermore, after chiral resolution, the crystallization temperature needs to be controlled within a specific range to directly obtain compound 1b with high purity and high optical purity in a single crystallization step.

[0012] This invention provides a method for preparing a high-purity citalopram S-diol intermediate. By optimizing the chiral resolution process, it breaks through the technical bias in the field that requires purification of precursor compound 1a and alkali-based recrystallization. The complex purification and alkali-based recrystallization steps for compound 1a are eliminated. Through precise parameter control in the compound 1b resolution stage, high-purity compound 1b can be prepared directly from crude compound 1a without the need for additional recrystallization purification. The prepared compound 1b exhibits high purity and high optical purity, and the yield is improved.

[0013] Preferably, the toluene residue in the evaporated substrate is ≤2%; more preferably, the toluene residue is ≤1%; more preferably, the toluene residue is 0.1-1%; even more preferably, the toluene residue is 0.5-1%.

[0014] Preferably, the water content of the anhydrous ethanol is ≤0.2%. By controlling the water content in the anhydrous ethanol, the purity of the product can be improved significantly.

[0015] Preferably, in step S2, during the process of adding acid to terminate the reaction, the pH of the reaction system is controlled at 6.5-8.0; more preferably, the pH of the reaction system is controlled at 7.0-7.5. Within this preferred pH range, the product salt can be better dissolved in the aqueous phase, and the reaction system is completely terminated with minimal product loss.

[0016] Preferably, in step S2, the reaction temperature for terminating the reaction is -10°C to 0°C.

[0017] Preferably, in step S2, at least one of the following (a) to (d) is selected: (a) The acid is hydrochloric acid; (b) The mass concentration of the acid is 10-38%; preferably, the mass concentration of the acid is 20-30%. (c) When adding acid, control the temperature of the reaction system to be between -15°C and -8°C; (d) After terminating the reaction, keep it at -2°C to 2°C with stirring.

[0018] Preferably, in step S3, the chiral resolution conditions further include a stirring speed of 125-135 rpm. At this preferred stirring speed, compound 1b obtained exhibits better yield, purity, and optical purity.

[0019] Preferably, in step S3, the mass-to-volume ratio of the evaporating substrate to the mixed solvent is 1g:5-10mL.

[0020] Preferably, in step S3, the mass-to-volume ratio of the crystalline product obtained after washing with anhydrous ethanol and maintaining the temperature for crystallization is 1g:3-5mL.

[0021] Preferably, in step S3, the chiral resolving agent is selected from at least one of D-di-p-methylbenzoyl tartaric acid, D-o-chloromandelic acid, and diethyl D-tartrate. More preferably, in step S3, the chiral resolving agent is selected from at least one of D-di-p-methylbenzoyl tartaric acid and D-o-chloromandelic acid. Under these preferred conditions, the chiral resolving effect is better.

[0022] Preferably, in step S3, the equivalence ratio of the evaporating substrate to the chiral resolving agent is 1:0.40-0.55; more preferably, the equivalence ratio is 1:0.45-0.50. Under these preferred conditions, the product has higher purity and optical purity.

[0023] Preferably, in step S3, the time for heat preservation and crystallization is 2-4 hours.

[0024] Preferably, in step S1, the preparation method of CPA-Mg includes the following steps: N,N-dimethylamino-3-chloropropane hydrochloride and alkaline solution are mixed and reacted, separated, and dried to obtain a crude CPA solution; under a nitrogen atmosphere, the crude CPA solution, toluene, 4-fluorobromobenzene, iodine catalyst and metallic magnesium undergo an exothermic reaction to prepare CPA-Mg; the specific reaction formula is shown below: .

[0025] Preferably, N,N-dimethylamino-3-chloropropane hydrochloride and alkaline solution are mixed and reacted at 40-50°C.

[0026] Preferably, the temperature of the exothermic reaction is 40-50℃.

[0027] Preferably, in step S1, the preparation method of BFB-Mg includes the following steps: under a nitrogen atmosphere, toluene, 4-fluorobromobenzene, metallic magnesium, and iodine catalyst are mixed and reacted, and then matured to obtain BFB-Mg; the specific reaction formula is shown below: .

[0028] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a method for preparing a high-purity citalopram S-diol intermediate. By optimizing the chiral resolution process, the yield, purity, and optical purity of compound 1b are improved. Furthermore, the crude compound 1a, after simple post-treatment, can be directly used in the reaction for chiral resolution, followed by one-step crystallization to prepare high-purity and high-optical-purity compound 1b. This eliminates the need for recrystallization of free base from compound 1a and the purification steps of recrystallization of crude compound 1b in existing processes, resulting in simple operation, high production efficiency, and low cost. Attached Figure Description

[0029] Figure 1 The image shows the 1H NMR spectrum of compound 1b from Example 1.

[0030] Figure 2 This is the carbon spectrum of compound 1b from Example 1.

[0031] Figure 3 This is a schematic diagram showing the purity of compound 1b in Example 1.

[0032] Figure 4 This is a schematic diagram showing the optical purity of compound 1b in Example 1.

[0033] Figure 5 This is a schematic diagram showing the purity of compound 1b in Example 2.

[0034] Figure 6 This is a schematic diagram showing the optical purity of compound 1b in Example 2.

[0035] Figure 7 This is a schematic diagram showing the purity of compound 1b in Example 3.

[0036] Figure 8 This is a schematic diagram showing the optical purity of compound 1b in Example 3.

[0037] Figure 9 This is a schematic diagram showing the purity of compound 1b in Example 4.

[0038] Figure 10 This is a schematic diagram showing the optical purity of compound 1b in Example 4.

[0039] Figure 11 This is a schematic diagram showing the purity of compound 1b in Example 5.

[0040] Figure 12 This is a schematic diagram showing the optical purity of compound 1b in Example 5.

[0041] Figure 13 This is a schematic diagram showing the purity of compound 1b in Example 6.

[0042] Figure 14 This is a schematic diagram showing the optical purity of compound 1b in Example 6.

[0043] Figure 15 This is a schematic diagram showing the purity of compound 1b in Example 7.

[0044] Figure 16 This is a schematic diagram showing the optical purity of compound 1b in Example 7.

[0045] Figure 17 This is a schematic diagram showing the purity of the crude compound 1b in Comparative Example 1.

[0046] Figure 18 This is a schematic diagram showing the optical purity of the crude compound 1b in Comparative Example 1.

[0047] Figure 19 This is a schematic diagram showing the purity of compound 1b in Comparative Example 1.

[0048] Figure 20 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 1.

[0049] Figure 21 This is a schematic diagram showing the purity of compound 1b in Comparative Example 2.

[0050] Figure 22 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 2.

[0051] Figure 23 This is a schematic diagram showing the purity of compound 1b in Comparative Example 4.

[0052] Figure 24 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 4.

[0053] Figure 25 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 5.

[0054] Figure 26 This is a schematic diagram showing the purity of compound 1b in Comparative Example 6.

[0055] Figure 27 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 6.

[0056] Figure 28 This is a schematic diagram showing the purity of compound 1b in Comparative Example 7.

[0057] Figure 29 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 7.

[0058] Figure 30 This is a schematic diagram showing the purity of compound 1b in Comparative Example 8.

[0059] Figure 31This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 8.

[0060] Figure 32 This is a schematic diagram showing the purity of compound 1b in Comparative Example 10.

[0061] Figure 33 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 10.

[0062] Figure 34 This is a schematic diagram showing the purity of compound 1b in Comparative Example 11.

[0063] Figure 35 This is a schematic diagram showing the optical purity of compound 1b in Comparative Example 11. Detailed Implementation

[0064] The present invention will be further described below with reference to the specification and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0065] Compound 1a was prepared according to the method described in the literature (DOI:10.1021 / acs.oprd.5c00188), and the specific reaction formula is shown below:

[0066] The specific operation includes the following steps: (1) Preparation of CPA-Mg: Stirring was started, and a solution of sodium hydroxide (113 g, 0.08 g / g) and deionized water (553 mL, 1.4 volume) was prepared in the reactor. After cooling to 20-30°C, N,N-dimethylamino-3-chloropropane hydrochloride (356 g) was added, and the mixture was heated to 40-50°C and maintained for 2 hours. The mixture was separated at room temperature, and the aqueous phase was discarded by bottom discharge, while the organic phase was collected in a polyethylene container. The organic phase was dried with fresh sodium hydroxide (113 g) at room temperature for 4 hours, and the moisture content was determined to be less than 0.2% by Karl Fischer method. It was then transferred to the reactor as crude CPA solution. To prepare the Grignard reagent, toluene (800 g), 4-fluorobromobenzene (54 g), iodine catalyst (2.79 g), and magnesium filings (68.2 g) were added to the nitrogen-purged reactor. After three nitrogen purgings, the mixture was heated to 45°C under light-protected conditions to initiate an exothermic reaction. The crude CPA solution was then introduced by controlled feeding, maintaining the temperature below 55°C. After the feeding was complete, the reaction was maintained at 55°C for 3 hours under light-protected conditions, and then cooled to room temperature under a nitrogen atmosphere to obtain CPA-Mg, which was used for subsequent reactions.

[0067] (2) Preparation of BFB-Mg: The anhydrous reactor was stirred and anhydrous toluene (1060 g) was added. After confirming the moisture content was below 0.06% by the Karl Fischer method, 4-fluorobromobenzene (54 g), magnesium chips (62 g), and iodine catalyst (2.45 g) were added sequentially under a nitrogen atmosphere. After three nitrogen purgings, the system was heated to 40°C under light-protected conditions to initiate the reaction, marked by decolorization and exothermic reaction. The remaining 4-fluorobromobenzene (358 g) was added by controlling the feed (keeping the temperature below 55°C), followed by aging at 50°C for 1 hour under light-protected conditions to obtain BFB-Mg. The resulting BFB-Mg solution was stable at 20-30°C under nitrogen protection for subsequent use.

[0068] (3) Preparation of compound 1a: Toluene (1600 g) was added to the reactor under a nitrogen atmosphere. After confirming the moisture content was below 0.06% by Karl Fischer titration, 5-cyanophthalide (446 g) was added. After three nitrogen purgings, the mixture was cooled to [temperature missing] under light-protected conditions. 10℃. Then add BFB-Mg and CPA-Mg solutions, keeping the internal temperature below 0℃. The reaction mixture is stirred at 0℃ for 1 hour until HPLC analysis shows that 5-cyanophthalide is completely consumed (residual <3%), at which point the reaction is complete and compound 1a is formed.

[0069] Example 1: A method for preparing high-purity S-diol A method for preparing high-purity S-diol specifically includes the following steps: (1) Preparation of crude compound 1a (post-processing): After the reaction of compound 1a was completed, 15.72 g of 36% dilute hydrochloric acid was added dropwise at -10℃ to quench the reaction. The pH of the system was controlled at 7.2 during the quenching process, and the system temperature was controlled at <0℃ throughout the process. After quenching, the mixture was kept at 0℃ and stirred for 1 h, followed by centrifugation and collection of the filtrate. The filtrate was transferred to a reaction vessel, heated to 75℃, and evaporated to dryness under reduced pressure. The distillation was continued for 3 h to obtain the substrate evaporated under reduced pressure (calculated by the external standard method, the substrate was 910.2 g, 1 eq, and the toluene residue in the substrate was 0.94%). The substrate was temporarily stored in the vessel.

[0070] The structural formula of compound 1a is: .

[0071] (2) Preparation (purification) of compound 1b: Anhydrous ethanol / 1,4-dioxane mixed solvent (mass-volume ratio of substrate to mixed solvent was 1 g: 6 mL; the volume percentage of dioxane in the mixed solvent was 16%) was added to the above-mentioned vacuum-evaporated substrate and stirred at room temperature until dissolved. Then, 0.47 eq of D-di-p-methylbenzoyl tartaric acid was added, and the reaction temperature was controlled at 40 °C, the stirring speed was 130 r / min, and the reaction was maintained at this temperature for 3 h. After the reaction was completed, the temperature was lowered to 13 °C at a rate of 2 °C / 10 min, and the mixture was kept at this temperature for 3 h to crystallize. The mixture was centrifuged at 2700 rpm, the filter cake was washed with anhydrous ethanol (4 volumes), and dried at 55 °C to obtain compound 1b.

[0072] The structural formula of compound 1b is: .

[0073] The overall yield of compound 1b was 47.7%, which is approximately 3% higher than the yield obtained by the latest process (reference (DOI:10.1021 / acs.oprd.5c00188)). The purity was 99.96%, the optical purity was 99.98%, and the isomer content was 0.02%. The 1H NMR spectrum, 1C NMR spectrum, purity diagram, and optical purity diagram of compound 1b are shown below. Figures 1 to 4 As shown.

[0074] Example 2: A method for preparing high-purity S-diol The difference between this embodiment and Embodiment 1 is that: In step (1), the pH of the quenching process is controlled at 7.5; the filtrate is transferred to the reaction vessel, heated to 80°C, and evaporated to dryness under reduced pressure; In step (2), the volume percentage of dioxane in the mixed solvent was 18%; 0.50 eq of D-di-p-methylbenzoyl tartaric acid was added, the reaction temperature was controlled at 45℃, the stirring speed was 135 r / min, and the reaction was maintained at this temperature for 3 h; after the reaction was completed, the temperature was lowered to 15℃ at a rate of 3℃ / 10 min, and the mixture was kept at this temperature for 3 h to crystallize, and then centrifuged. The filter cake was washed with anhydrous ethanol (5 volumes) and dried at 55℃ to obtain compound 1b.

[0075] The overall yield of compound 1b was 47.4%, with a purity of 99.90%, an optical purity of 99.97%, and an isomer content of 0.03%. The purity and optical purity diagrams of compound 1b are shown below. Figures 5 to 6 As shown.

[0076] Example 3: A method for preparing high-purity S-diol The difference between this embodiment and Embodiment 1 is that: In step (1), the pH of the quenching process is controlled at 7.0; the filtrate is transferred to the reaction vessel, heated to 70°C, and evaporated to dryness under reduced pressure; In step (2), the volume percentage of dioxane in the mixed solvent is 13%; 0.45 eq of D-di-p-methylbenzoyl tartaric acid is added, the reaction temperature is controlled at 35℃, the stirring speed is 125 r / min, and the reaction is maintained at this temperature for 3 h; after the reaction is completed, the temperature is lowered to 10℃ at a rate of 1℃ / 10 min, and the mixture is kept at this temperature for 3 h to crystallize, and then centrifuged. The filter cake is washed with anhydrous ethanol (3 volumes) and dried at 55℃ to obtain compound 1b.

[0077] The overall yield of compound 1b was 47.5%, with a purity of 99.81%, an optical purity of 99.98%, and an isomer content of 0.02%. The purity and optical purity diagrams of compound 1b are shown below. Figures 7 to 8 As shown.

[0078] Examples 4-5 The difference between Example 4 and Example 1 is that in step (1), the pH of the quenching process is controlled at 6.5.

[0079] The difference between Example 5 and Example 1 is that in step (1), the pH of the quenching process is controlled to be 8.

[0080] The purity diagram and optical purity diagram of compound 1b in Example 4 are shown below. Figures 9 to 10 As shown. The purity diagram and optical purity diagram of compound 1b in Example 5 are shown below. Figures 11 to 12 As shown.

[0081] Examples 6-7 The difference between Example 6 and Example 1 is that in step (2), 0.40 eq of D-di-p-methylbenzoyl tartaric acid is subsequently added.

[0082] The difference between Example 7 and Example 1 is that in step (2), 0.55 eq of D-di-p-methylbenzoyl tartaric acid is subsequently added.

[0083] The purity diagram and optical purity diagram of compound 1b in Example 6 are shown below. Figures 13 to 14 As shown. The purity diagram and optical purity diagram of compound 1b in Example 7 are shown below. Figures 15 to 16 As shown.

[0084] Comparative Example 1 The post-treatment and chiral resolution of compound 1a in Comparative Example 1, and the preparation of compound 1b, were carried out according to the literature (DOI:10.1021 / acs.oprd.5c00188), and the specific procedures were as follows: (1) Preparation of crude compound 1a (post-processing): In Quenching was performed at 10°C by dropwise addition of 36% hydrochloric acid (temperature maintained below 0°C). After stirring at 0°C for 1 hour, the mixture was heated to 25±5°C for phase separation. The organic phase was concentrated under reduced pressure at 80°C. It was then diluted with toluene (25.66 g) and heated to 65°C to homogenize. The solution was cooled to... Add n-heptane (49.6 g) at 5 °C. After crystallization for 1 hour, separate the solid by centrifugation, wash with n-heptane (12 g), and dry at 35 °C for 10 hours to obtain compound 1a.

[0085] (2) Preparation of compound 1b: 310 g of 1,4-dioxane was added to the reactor containing compound 1a and dissolved. 960 g of 1,4-dioxane and 34.8 g of D-di-p-tolyl tartaric acid were added to another reactor. The mixture was slowly heated to 35°C and stirred until homogeneous. Under conditions of thermal equilibrium, the dioxane solution of D-di-p-tolyl tartaric acid was transferred to the reactor containing compound 1a. The resulting mixture was kept at 35°C for 2 hours and then cooled to 25°C. The crude product of compound 1b was obtained by filtration.

[0086] The purity of the crude compound 1b was 97.13%, the optical purity was 94.73%, and the isomer content was 5.27%. The purity and optical purity diagrams of the crude compound 1b are shown below. Figures 17 to 18 As shown.

[0087] (3) Add 482g of anhydrous ethanol to the reaction vessel containing the crude compound 1b, start stirring, and keep stirring at 25-30℃ for 3h. Then cool the reaction system to -10℃, keep stirring for 2h, centrifuge, and dry the wet product at 45℃ for 8h to obtain compound 1b.

[0088] The overall yield of compound 1b was 44.3%, which is about 3% lower than that of this invention. The purity was 99.78%, the optical purity was 99.96%, and the isomer content was 0.04%, meeting European, American, and Japanese quality standards. The purity and optical purity diagrams of compound 1b are shown below. Figure 19 and Figure 20 As shown.

[0089] Comparative Examples 2-3 The difference between Comparative Example 2 and Example 1 is that in step (1), the temperature is raised to 85°C and evaporated to dryness under reduced pressure.

[0090] The difference between Comparative Example 3 and Example 1 is that in step (1), the temperature is raised to 65°C and evaporated to dryness under reduced pressure.

[0091] In Comparative Example 3, the deevaporation rate was relatively slow, and it was difficult to meet the requirement that the toluene residue was below 3.0% (the actual toluene residue was 6.9%). The total yield of compound 1b was 40.4%, the purity was 97.42%, and the optical purity was 96.14%.

[0092] The purity diagram and optical purity diagram of compound 1b in Comparative Example 2 are shown below. Figures 21 to 22 As shown.

[0093] Comparative Example 4 The difference between Comparative Example 4 and Example 1 is that in step (1), the substrate toluene residue was reduced to 5.2% by vacuum evaporation.

[0094] The purity diagram and optical purity diagram of compound 1b in Comparative Example 4 are shown below. Figures 23 to 24 As shown.

[0095] Comparative Examples 5-6 The difference between Comparative Example 5 and Example 1 is that in step (2), dioxane accounts for 25%.

[0096] The difference between Comparative Example 6 and Example 1 is that in step (2), dioxane accounts for 8%.

[0097] Schematic diagrams of the optical purity of compound 1b in Comparative Example 5 are shown below. Figure 25 As shown. The purity diagram and optical purity diagram of compound 1b in Comparative Example 6 are shown below. Figures 26 to 27 As shown.

[0098] Comparative Examples 7-8 The difference between Comparative Example 7 and Example 1 is that in step (2), D-di-p-methylbenzoyl tartaric acid was added and the reaction temperature was controlled at 30°C.

[0099] The difference between Comparative Example 8 and Example 1 is that in step (2), D-di-p-methylbenzoyl tartaric acid was added and the reaction temperature was controlled at 50°C.

[0100] The purity diagram and optical purity diagram of compound 1b in Comparative Example 7 are shown below. Figures 28 to 29 As shown. The purity diagram and optical purity diagram of compound 1b in Comparative Example 8 are shown below. Figures 30 to 31 As shown.

[0101] Comparative Example 9 The difference between Comparative Example 9 and Example 1 is that in step (2), the temperature is reduced to 5°C at a rate of 2°C / 10min.

[0102] When the crystallization temperature is below 10℃, the dioxane in the mixed solvent is easy to solidify, and the solid is relatively sticky during the centrifugation stage, making it difficult to carry out subsequent centrifugation operations.

[0103] Comparative Example 10 This comparative example was prepared using the crude compound 1a from Example 1, employing the chiral resolution process described in the literature (DOI:10.1021 / acs.oprd.5c00188), specifically including the following steps: (1) Preparation of crude compound 1a (post-processing): Refer to step (1) in Example 1; (2) Preparation of compound 1b: Following step (2) in Comparative Example 1, crude compound 1b was obtained; The purity diagram and optical purity diagram of the crude compound 1b in Comparative Example 10 are shown below. Figures 32 to 33 As shown, the overall yield of compound 1b was 41.3%, the purity was 88.62%, the optical purity was 92.23%, and the isomer content was 7.77%. Compound 1b has low purity and optical purity, contains many impurities, and cannot be used directly. Moreover, it cannot be purified to meet the required quality standards.

[0104] Comparative Example 11 This comparative example uses the crude product of compound 1a from Example 1, employs the chiral resolution process described in the literature (DOI:10.1021 / acs.oprd.5c00188), and compound 1b is prepared using one-step crystallization. The specific steps include: (1) Preparation of crude compound 1a (post-processing): Refer to step (1) in Example 1; (2) Preparation of compound 1b: Refer to step (2) of Comparative Example 1, except that after the reaction, the one-step crystallization operation in Example 1 is used. Specifically, in step (2) of Comparative Example 1, after the mixture is kept at 35°C for 2 hours, it is cooled to 13°C at a rate of 2°C / 10min and kept at that temperature for 3 hours to crystallize. Then, it is centrifuged at 2700 rpm. The filter cake is washed with anhydrous ethanol (4 volumes) and dried at 55°C to obtain compound 1b.

[0105] The purity diagram and optical purity diagram of compound 1b in Comparative Example 11 are shown below. Figures 34 to 35 As shown. The overall yield of compound 1b was 42.7%, the purity was 96.36%, the optical purity was 94.85%, and the isomer content was 5.15%.

[0106] In the examples and comparative examples, the purity and optical purity of the finally obtained compound 1b are shown in Table 1 below.

[0107] Table 1

[0108] As shown in Table 1 above, the compound 1b prepared by the method provided by the present invention has a purity ≥ 99.15% and an optical purity ≥ 99.79%. More preferably, the purity of compound 1b is ≥ 99.81% and the optical purity is ≥ 99.97%.

[0109] As can be seen from Example 1 and Comparative Example 1, the preparation of compound 1b using the existing process not only requires more complex operations, but also requires solvent dissolution and free base recrystallization for the purification of compound 1a. Furthermore, the obtained compound 1b is still difficult to meet the requirements, and further purification by ethanol recrystallization is needed to achieve the required purity and optical purity of the product.

[0110] As can be seen from Examples 1, 2, 3 and 4, when the heating temperature is high, the purity and optical purity of compound 1b are difficult to meet the actual requirements; while when the heating temperature is low, the toluene residue is difficult to meet the requirement of being below 3.0%, which affects the operation during the chiral separation process, and the purity and optical purity of compound 1b are difficult to meet the actual requirements.

[0111] As shown in Examples 1, 5, and 6, when the proportion of dioxane in the system is low, the separation effect is poor, and the optical purity of the separated product is difficult to meet the actual requirements. When the proportion of dioxane is high, not only is the separation effect poor, but the impurity removal effect is also weakened, and the purity and optical purity of the product do not meet the requirements.

[0112] As shown in Examples 1, 7, and 8, when the resolution temperature is low, the resolving agent has difficulty completely resolving compound 1a, the yield of compound 1b is significantly reduced, the optical purity does not meet the quality standards, and the resolution effect deteriorates. When the resolution temperature is high, the resolving agent has poor selectivity for compound 1b, and isomers also precipitate simultaneously, failing to meet the high optical purity standard.

[0113] As shown in Example 1 and Comparative Example 10, the crude compound 1a was processed using the method of the present invention, but the separation effect was still poor when using existing separation processes. This indicates that under existing separation conditions, compound 1a still requires complex post-processing to ensure the effectiveness of subsequent separation processes.

[0114] As can be seen from Example 1 and Comparative Example 11, even after performing a one-step crystallization step following the existing splitting process, the purity and optical purity of the final product still do not meet the requirements.

[0115] Table 2 shows a process comparison between the process of the present invention and the existing process (Comparative Example 1).

[0116] Table 2

[0117] As shown in Table 2, the crude compound 1a in this invention can be chirally resolved after simple post-processing to directly prepare compound 1b with high purity and high optical purity. At the same time, the recrystallization of free base of compound 1a and the recrystallization purification process of crude compound 1b are omitted, which makes the operation simple, the production efficiency high and the cost low.

[0118] The foregoing examples are merely illustrative, used to explain some features of the method described in this invention. The appended claims are intended to claim the broadest possible scope, and the embodiments presented herein are demonstrated by the applicant's actual experimental results. Therefore, the applicant intends that the appended claims are not limited by the selection of examples illustrating the features of the invention. Some numerical ranges used in the claims also include sub-ranges within them, and variations within these ranges should also be interpreted as being covered by the appended claims where possible.

Claims

1. A method for preparing a citalopram S-diol intermediate, characterized in that, Includes the following steps: S1. Under a nitrogen atmosphere, 5-cyanophthalide, BFB-Mg, CPA-Mg and toluene react to produce racemic citalopram diol intermediate 1a; S2. Post-treatment: The reaction was terminated by adding acid to the racemic citalopram diol intermediate, centrifuged to obtain the filtrate, and the filtrate was evaporated under reduced pressure at 70-80℃ to obtain an evaporated substrate with ≤3% toluene residue; S3. Chiral resolution and purification: Evaporate the substrate and mix with the mixed solvent, add the chiral resolving agent, and carry out chiral resolution at 35-45℃; after the reaction is completed, cool to 10-15℃, keep warm to crystallize, wash and dry to obtain the citalopram S-diol intermediate; In step S1, the reaction formula is as follows: ； In step S3, the mixed solvent is a mixture of anhydrous ethanol and 1,4-dioxane, and the volume percentage of 1,4-dioxane in the mixed solvent is 13-18%. The structural formula of the citalopram S-diol intermediate is: ； In step S2, during the process of adding acid to terminate the reaction, the pH of the reaction system is controlled to be 7.0-7.

5. In step S3, the chiral resolving agent is selected from D-di-p-methylbenzoyl tartaric acid.

2. The preparation method according to claim 1, characterized in that, In step S2, the acid is hydrochloric acid.

3. The preparation method according to claim 1, characterized in that, In step S2, the mass concentration of the acid is 10-38%.

4. The preparation method according to claim 1, characterized in that, In step S2, when acid is added, the temperature of the reaction system is controlled to be between -15°C and -8°C.

5. The preparation method according to claim 1, characterized in that, In step S2, after the reaction is terminated, the mixture is kept at -2°C to 2°C and stirred.

6. The preparation method according to claim 1, characterized in that, In step S3, the conditions for chiral separation also include a stirring speed of 125-135 rpm.

7. The preparation method according to claim 1, characterized in that, In step S3, the mass-to-volume ratio of the evaporating substrate to the mixed solvent is 1g:5-10mL.

8. The preparation method according to claim 1, characterized in that, In step S3, the mass-to-volume ratio of the crystalline product obtained after washing with anhydrous ethanol and maintaining the temperature for crystallization is 1g:3-5mL.

9. The preparation method according to claim 1, characterized in that, In step S3, the cooling rate is 1-3℃ / 10min.

10. The preparation method according to claim 1 or 9, characterized in that, In step S3, the equivalence ratio of the evaporating substrate to the chiral resolving agent is 1:0.40-0.

55.

11. The preparation method according to claim 1, characterized in that, In step S3, the time for heat preservation and crystallization is 2-4 hours.

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