Method for preparing s-citalopram

Abstract

The present invention relates to a method for preparing S-citalopram on the basis of an R-diol intermediate. The method comprises the following steps: (1) under the action of a sterically hindered acid and a sterically hindered ligand, subjecting a citalopram R-diol intermediate to SN2 configuration inversion to obtain a mixture containing S-citalopram and R-citalopram; and (2) subjecting the mixture in step (1) to a resolving agent to obtain S-citalopram. In addition, further disclosed in the present invention is a method for preparing S-citalopram. The optical purity of the S-citalopram prepared by the method of the present invention is greater than 95% and is greater than 99% after purification. In addition, the overall yield of the S-citalopram is increased from 31% in a conventional process to up to 82%.

Description

A method for preparing S-citalopram Technical Field

[0001] This invention belongs to the technical field of drug preparation; more specifically, it relates to a method for preparing S-citalopram. Background Technology

[0002] Escitalopram oxalate, also known as citalopram, chemically named S-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran oxalate, is a novel selective serotonin reuptake inhibitor jointly developed by Forest Laboratories in the United States and Lundbeck in Denmark. It was launched in the United States in August 2002 and is currently the most selective antidepressant used clinically. Compared with other first-line antidepressants such as fluoxetine, venlafaxine, and sertraline, this drug not only has advantages such as high selectivity, rapid treatment speed, and fewer adverse reactions, but also has demonstrated outstanding performance in treating depression and anxiety in clinical trials, making escitalopram oxalate a rising star in the field of antidepressants.

[0003] Citalopram exists as a chiral isomer. Currently, the single dextrorotatory optical isomer of citalopram, S-citalopram (also known as dextrorotatory citalopram), is known to have an antidepressant effect at least 100 times stronger than R-citalopram (also known as levorotatory citalopram). Furthermore, S-citalopram exhibits higher selectivity for 5-HT reuptake inhibition compared to racemic citalopram, has lower affinity for other receptors, resulting in better efficacy, fewer side effects, and a dosage reduction of half. Therefore, S-citalopram has gained widespread use.

[0004] Since its market launch, citalopram has been synthesized primarily through chiral resolution, chiral source synthesis, and asymmetric catalysis. Among these, chiral resolution is currently the main industrial method for preparing S-citalopram. Chiral resolution involves using a resolving agent to separate the racemic diol intermediate of citalopram (its structure is shown below, also known as the diol) to obtain the citalopram S-diol intermediate (its structure is shown below, also known as S-diol) and the citalopram R-diol intermediate (its structure is shown below, also known as R-diol). The S-diol intermediate is then subjected to a ring-closing reaction to prepare S-citalopram. However, the byproduct R-diol intermediate is primarily discharged as waste, resulting in low atom utilization, low overall yield, and high production costs for citalopram.

[0005] To address the above issues, patent publication number CN101440079A discloses a method for obtaining a mixture of S-citalopram and R-citalopram by cyclizing a mixture of more than 50% R-diol and S-diol under acidic conditions through configuration inversion, wherein the highest proportion of S-citalopram (i.e., optical purity) is less than 75%. Then, the target product (S-citalopram) is separated by precipitation crystallization, taking advantage of the difference in solubility of S-citalopram and R-citalopram in different solvents. The main problems with this method are as follows: First, the proportion of R-diol that undergoes configuration inversion to S-citalopram under acidic conditions is relatively low. Second, the highest proportion of S-citalopram after conversion is less than 75%, and the optical purity of S-citalopram obtained by precipitation crystallization is low (ee value < 95%), failing to meet the standards of various countries (ee > 98%). The yield after purification is low, less than 10%, which is not conducive to industrialization.

[0006] Patent publication number CN1729164A discloses a method for separating a mixture of R-diol and S-diol with enantiomers exceeding 50%, which is then converted into a mixture of S-citalopram and R-citalopram through configurational inversion, followed by multiple recrystallization purifications to separate S-citalopram. This method yields S-citalopram with low optical purity (ee value < 95%), and the post-processing is extremely cumbersome, requiring multiple recrystallization purifications, resulting in a very low overall yield. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention aims to provide a method for preparing S-citalopram based on R-diol intermediates. This preparation method not only achieves a high configuration conversion yield but also yields S-citalopram with high optical purity.

[0008] The second objective of this invention is to provide a method for preparing S-citalopram.

[0009] The above-mentioned objectives of the present invention are achieved through the following technical solutions.

[0010] This invention claims protection for a method for preparing S-citalopram based on an R-diol intermediate, comprising the following steps:

[0011] (1) The citalopram R-diol intermediate undergoes SN2 configuration inversion under the action of sterically hindered acid and sterically hindered ligand to obtain a mixture containing S-citalopram and R-citalopram.

[0012] The terrestrial barrier acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid, or hydroiodic acid.

[0013] The sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1Hpyrazole or n-butylbis(1-adamantyl)phosphine;

[0014] The optical purity of the citalopram R-diol intermediate is ≥80%;

[0015] (2) The mixture after step (1) is treated with a resolving agent to obtain S-citalopram.

[0016] This invention provides a novel method for preparing S-citalopram based on R-diol intermediates. The citalopram R-diol intermediate undergoes configurational inversion cyclization under the action of a sterically hindered acid and a sterically hindered ligand to obtain S-citalopram. The obtained product has an ee value greater than 95%, significantly higher than the purity of S-citalopram obtained by existing methods (the optical purity of S-citalopram is less than 75%). Subsequent post-treatment with a resolving agent results in purified S-citalopram with an optical purity greater than 99% and a configurational conversion yield ≥46%.

[0017] Furthermore, the inventors discovered through research that in the present application, it is necessary to use an acid with large steric hindrance and a ligand with large steric hindrance to cooperate in order to effectively improve the efficiency of configuration inversion cyclization and improve the optical purity of S-citalopram. Only then can the optical purity of the purified S-citalopram be greater than 99%, thereby achieving the technical effect of the present invention. It is difficult to achieve the technical effect of the present invention by using other types of acids or ligands.

[0018] This invention solves the current problem of the inability to further utilize the citalopram R-diol intermediate, enabling the preparation of S-citalopram from the citalopram R-diol intermediate through configurational transformation, with significantly improved optical purity and configurational transformation yield. The method described in this invention addresses the problems of low optical purity, low separation yield, low atom utilization, and high production cost in the separation and purification of S-citalopram.

[0019] Preferably, in step (1), the steric hindrance acid is one or both of hydrobromic acid and hydroiodic acid. Under this preferred method, the resulting mixture exhibits higher optical purity of S-citalopram.

[0020] Preferably, in step (1), in order to obtain a high optical purity citalopram R-diol intermediate, the citalopram diol racemic mixture can be obtained by multiple resolutions, or a mixture of citalopram R-diol intermediate and citalopram S-diol intermediate can be directly used for resolution.

[0021] Specifically, in step (1), the optical purity of the citalopram R-diol intermediate is ≥90%. Preferably, the optical purity is ≥92%; more preferably, the optical purity is ≥98%.

[0022] Specifically, the citalopram diol racemic mixture is used for resolution at least twice. More specifically, in some embodiments, the citalopram diol racemic mixture can be first resolved using a D-resolving agent, followed by resolution of the mother liquor using an L-resolving agent to obtain a citalopram R-diol intermediate with high optical purity.

[0023] Specifically, when resolving directly using a mixture of citalopram R-diol intermediate and citalopram S-diol intermediate, the resolving agent used is an L-resolving agent. More specifically, the resolving agent can be an L-resolving agent conventionally used in the art for configurational conversion. More specifically, the resolving agent is selected from one or more of L-dibenzoyl tartaric acid, L-di-p-methylbenzoyl tartaric acid, or diethyl L-tartrate.

[0024] Specifically, in the mixture of citalopram R-diol intermediate and citalopram S-diol intermediate, the optical purity of citalopram R-diol intermediate is ≥40%; more preferably, the optical purity is ≥50%; more preferably, the optical purity is ≥60%; even more preferably, the optical purity is 60-99%; more specifically, the optical purity of citalopram R-diol intermediate can be at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, etc., or any range formed by the above values, such as 50-90%, 60-99%, etc., and the present invention is not limited thereto.

[0025] Preferably, in step (2), the resolving agent is a D-resolving agent. More specifically, the resolving agent can be a D-resolving agent conventionally used in the art for configurational conversion. More specifically, the resolving agent is selected from one or more of D-dibenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, or diethyl D-tartrate.

[0026] Preferably, in step (1), the solvent used can be one or more of toluene or ethanol.

[0027] Preferably, in step (1), the mass ratio of citalopram R-diol intermediate to sterically hindered acid is 1:1.7-2.1.

[0028] Preferably, in step (1), the molar ratio of the citalopram R-diol intermediate to the sterically hindered ligand is 1:0.05-0.08.

[0029] Preferably, in step (1), the reaction temperature is 40-50℃.

[0030] Preferably, in step (1), the reaction time is 3-5 hours.

[0031] Preferably, in step (2), the reaction temperature is 50-60℃.

[0032] Preferably, in step (2), the solvent used can be one or more of anhydrous ethanol, anhydrous acetonitrile, or anhydrous acetone.

[0033] Preferably, in step (2), the mass ratio of the resolving agent to the mixture after treatment in step (1) is 0.15-0.35:10.

[0034] Furthermore, this invention claims protection for a method for preparing S-citalopram, comprising the following steps:

[0035] S1. The racemic citalopram diol was separated by chiral resolution. The separated citalopram S-diol intermediate precipitated from the reaction system, and the mixture of citalopram R-diol intermediate and part of citalopram S-diol intermediate was enriched in the mother liquor of the separation.

[0036] S2. The mother liquor was separated by chiral resolution to obtain citalopram R-diol intermediate;

[0037] S3. In step S2, the citalopram R-diol intermediate undergoes an SN2 configuration inversion under the action of a sterically hindered acid and a sterically hindered ligand, yielding a mixture containing S-citalopram and R-citalopram.

[0038] Wherein, the steric hindrance acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid;

[0039] The sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1Hpyrazole or n-butylbis(1-adamantyl)phosphine;

[0040] S4. The mixture in step S3 is separated by chiral resolution to obtain S-citalopram;

[0041] S5. The citalopram S-diol intermediate precipitated in step S1 undergoes a ring-closing reaction to obtain S-citalopram.

[0042] The reaction formula for the preparation of S-citalopram is shown in the figure below:

[0043] This invention provides a novel method for preparing S-citalopram. First, a racemic diol intermediate is resolved using a chiral resolution method to obtain a mother liquor containing the R-diol intermediate. Then, the mother liquor containing the R-diol intermediate is further resolved using a chiral resolution method to obtain an R-diol intermediate with high optical purity. Furthermore, the high-optical-purity R-diol intermediate, under the combined action of a sterically hindered acid and a sterically hindered ligand, undergoes configuration inversion cyclization via an SN2 mechanism to form S-citalopram. The obtained S-citalopram has an optical purity greater than 95%, solving the technical problem of insufficient optical purity (less than 75%) in the conversion of R-diol to S-citalopram in existing methods. Further, the obtained S-citalopram is further resolved to obtain S-citalopram with an optical purity greater than 99%. Finally, the S-diol intermediate precipitated in step S1 undergoes a ring-closure reaction to obtain S-citalopram.

[0044] The total yield of S-citalopram (step S4 + step S5) obtained by the above method of the present invention is higher than 75%, and can be increased to a maximum of 82%.

[0045] The method described in this invention solves the problems encountered in the current conversion of high optical purity R-diol intermediates into S-citalopram, including low optical purity (less than 75%), still low optical purity of purified S-citalopram (ee < 95%), and low separation yield. This method can greatly promote industrial upgrading and significantly reduce the overall production cost of citalopram.

[0046] More specifically, in some more specific embodiments, this invention claims protection for a method for preparing S-citalopram, comprising the following steps:

[0047] S1. The racemic citalopram diol, resolving agent, and solvent are mixed. The separated citalopram S-diol intermediate precipitates from the reaction system, and the mixture of citalopram R-diol intermediate and part of the citalopram S-diol intermediate is enriched in the resolving mother liquor.

[0048] S2. The mother liquor, resolving agent and solvent described in step S1 are mixed to obtain citalopram R-diol intermediate;

[0049] S3. Step S2: The citalopram R-diol intermediate, the sterically hindered acid, and the sterically hindered ligand react together, resulting in an SN2 configuration inversion to obtain a mixture containing S-citalopram and R-citalopram.

[0050] S4. The mixture, resolving agent, and solvent in step S3 are mixed to obtain S-citalopram;

[0051] Wherein, the steric hindrance acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid;

[0052] The sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1Hpyrazole or n-butylbis(1-adamantyl)phosphine;

[0053] S5. The citalopram S-diol intermediate precipitated in step S1, acyl chloride reagent, base and solvent are mixed and subjected to a ring-closing reaction to obtain S-citalopram.

[0054] Preferably, in step S1, the resolving agent can be a D-resolving agent conventionally used in the art for configurational conversion. More specifically, the resolving agent is selected from one or more of D-dibenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, and diethyl D-tartrate.

[0055] Preferably, in step S1, the solvent is isopropanol, the reaction temperature is 20-30℃, and the reaction time is 10-12h.

[0056] Preferably, in step S1, the mass ratio of the resolving agent to the citalopram racemic diol intermediate is 0.25-0.35:10.

[0057] Preferably, in step S2, the resolving agent can be an L-resolving agent conventionally used in the art for configurational conversion. More specifically, the resolving agent is selected from one or more of L-dibenzoyl tartaric acid, L-di-p-methylbenzoyl tartaric acid, or diethyl L-tartrate.

[0058] Preferably, in step S2, the solvent is one or more of ethanol, isopropanol, or dioxane.

[0059] Preferably, in step S2, the reaction time is 6-8 hours.

[0060] Preferably, in step S2, the reaction temperature is 20-30℃.

[0061] Preferably, in step S2, the mass ratio of the resolving agent to the mixture is 0.18-0.25:1.

[0062] Preferably, in step S3, the solvent is one or more of toluene or ethanol.

[0063] Preferably, in step S3, the mass ratio of the citalopram R-diol intermediate to the sterically hindered acid is 1:1.7-2.1.

[0064] Preferably, in step S3, the molar ratio of the citalopram R-diol intermediate to the sterically hindered ligand is 1:0.05-0.08.

[0065] Preferably, in step S3, the reaction temperature is 40-50℃.

[0066] Preferably, in step S3, the reaction time is 3-5 hours.

[0067] Preferably, in step S4, the reaction temperature is 50-60℃.

[0068] Preferably, in step S4, the reaction solvent is one or more of anhydrous ethanol, anhydrous acetonitrile, or anhydrous acetone.

[0069] Preferably, in step S4, the mass ratio of the resolving agent to the mixture of S-citalopram and R-citalopram in step S3 is 0.15-0.35:10.

[0070] Preferably, in step S4, the resolving agent can be a D-resolving agent conventionally used in the art for configurational conversion. More specifically, the resolving agent is selected from one or more of D-dibenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, and diethyl D-tartrate.

[0071] Preferably, in step S5, the acyl chloride reagent is selected from one or more of p-toluenesulfonyl chloride and acetyl chloride.

[0072] Preferably, in step S5, the alkali is selected from one or more of ammonia, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, methylamine, diisopropylethylamine, or pyridine.

[0073] Preferably, in step S5, the solvent is toluene.

[0074] Compared with the prior art, the present invention has the following beneficial effects:

[0075] (1) This invention provides a new method for preparing S-citalopram based on R-diol intermediates. S-citalopram is prepared by cyclization of the R-diol intermediate under the action of a sterically hindered acid and a sterically hindered ligand. The optical purity of the obtained S-citalopram is greater than 95%, which solves the technical problem of insufficient configuration conversion rate (less than 75%) of S-citalopram in existing methods. In addition, the optical purity of the purified S-citalopram is greater than 99%, which meets the standards of various countries.

[0076] (2) The present invention provides a new method for preparing S-citalopram. The total yield of S-citalopram (step S4 + step S5) obtained by the above method of the present invention is higher than 75%, and can be increased to 82% at most; and the optical purity of the prepared S-citalopram is greater than 99%. Attached Figure Description

[0077] Figure 1 shows the optical purity of compound 2b in step (2) of Example 1.

[0078] Figure 2 shows the optical purity of the mixture of compound 3a and compound 3b in step (3) of Example 1.

[0079] Figure 3 shows the 1H NMR spectrum of compound 3a in step (3) of Example 1.

[0080] Figure 4 shows the carbon NMR spectrum of compound 3a in step (3) of Example 1.

[0081] Figure 5 shows the optical purity of compound 3a obtained after purification in step (4) of Example 1.

[0082] Figure 6 shows the optical purity of compound 3 obtained by replacing benzenesulfonic acid with hydrobromic acid and using 18-crown-6 as a ligand.

[0083] Figure 7 shows the optical purity of compound 3 obtained by replacing benzenesulfonic acid with hydroiodic acid and using 18-crown-6 as a ligand.

[0084] Figure 8 shows the optical purity of compound 3 obtained by replacing benzenesulfonic acid with methanesulfonic acid and using 18-crown-6 as a ligand.

[0085] Figure 9 shows the optical purity of compound 3 obtained by replacing 18-crown-6 with 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthylene.

[0086] Figure 10 shows the optical purity of compound 3 obtained by replacing 18-crown-6 with 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazol.

[0087] Figure 11 shows the optical purity of compound 3 obtained by replacing 18-crown-6 with n-butyldi(1-adamantyl)phosphine.

[0088] Figure 12 shows the optical purity of compound 3a obtained by replacing D-dibenzoyl tartaric acid with D-dimethylbenzoyl tartaric acid.

[0089] Figure 13 shows the optical purity of compound 3a obtained by replacing D-dibenzoyl tartaric acid with diethyl D-tartrate.

[0090] Figure 14 shows the optical purity of compound 3a obtained by using D-dibenzoyl tartaric acid as a resolving agent and replacing anhydrous ethanol with anhydrous acetonitrile.

[0091] Figure 15 shows the optical purity of compound 3a obtained by using D-dibenzoyl tartaric acid as a resolving agent and replacing anhydrous ethanol with anhydrous acetone.

[0092] Figure 16 shows the optical purity of the mixture of compounds 3a and 3b obtained by replacing benzenesulfonic acid with dilute sulfuric acid.

[0093] Figure 17 shows the optical purity of compound 3a obtained after purification using dilute sulfuric acid instead of benzenesulfonic acid. Detailed Implementation

[0094] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details. The various embodiments described below are made with the understanding that this disclosure is intended to be illustrative of the claimed subject matter and not to limit the appended claims to the specific embodiments described. Headings used throughout this disclosure are merely for convenience and are not to be construed as limiting the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0095] Example 1: Preparation of S-Citalopram

[0096] The reaction formula and reaction steps are shown below:

[0097] (1) Synthesize compounds 2a and 2b

[0098] At room temperature, 10 g of compound 1, 310 mg of resolving agent D-benzoyl tartaric acid, and 120 mL of isopropanol were added sequentially to a 500 mL three-necked flask. The reaction was maintained at 25 °C for 11 h. After the reaction was completed, compound 2a (S-diol) was obtained by filtration. The separation yield of compound 2a was 35% based on compound 1. The remaining mother liquor (mainly a mixture of citalopram R-diol intermediate and citalopram S-diol intermediate, wherein the optical purity of citalopram R-diol intermediate was 60-65%) was evaporated to dryness and set aside for later use.

[0099] (2) Synthesis of compound 2b

[0100] Add 110 mL of ethanol to the pre-evaporated substrate from step (1), then slowly add 160 mg of the resolving agent L-benzoyl tartaric acid, and react at 25 °C for 7 h. After the reaction is complete, filter directly to obtain R-diol with high optical purity (i.e., compound 2b). Dry the crude product and set aside for later use. Based on the citalopram R-diol intermediate from step (1), the separation yield of compound 2b is 91%; as shown in Figure 1, the optical purity of R-diol is 92.39%.

[0101] (3) Synthesize a mixture of compound 3a and compound 3b

[0102] At room temperature, 10 g of compound 2b, 150 mL of toluene, 21 g of benzenesulfonic acid, and 220 mg of the sterically hindered ligand 18-crown-6 were added sequentially to a 250 mL three-necked flask. The reaction system was heated to 45 °C and maintained at this temperature for 4 h. After the reaction was completed, the temperature was lowered to 10-15 °C, and the mixture was directly filtered and dried to obtain a mixture of compounds 3a and 3b, with a mass of 8.23 ​​g. Based on compound 2b, the yield of the mixture was 86.9%. The optical purity is shown in Figure 2. The optical purity of compound 3a was 95.48%, and the optical purity of compound 3b was 4.52%.

[0103] (4) Purification of compound 3a

[0104] A mixture of 20 g of compounds 3a and 3b was added to a 500 mL reaction flask at room temperature, followed by 300 mL of anhydrous ethanol. The mixture was stirred at room temperature for 10 min. Then, 330 mg of the resolving agent D-dibenzoyl tartaric acid was added, and the temperature was raised to 55 °C and maintained for 2.5 h. After the reaction was complete, the temperature was lowered to -15 °C and maintained for 1 h. The mixture was then filtered, and the filter cake was dried to obtain 10.2 g of compound 3a with high optical purity. The configurational conversion yield of compound 3a was 51% based on the mixture. The 1H and 1C NMR spectra of compound 3a are shown in Figures 3 and 4, respectively. The optical purity is shown in Figure 5; the optical purity of compound 3a was 99.92%, and that of compound 3b was 0.08%.

[0105] (5) Synthesis of compound 3a

[0106] Compound 2a, obtained by separation and filtration in step (1), 3.6 g of triethylamine, and 100 mL of toluene were added sequentially to a 500 mL reaction flask at room temperature. P-Toluenesulfonyl chloride was then slowly added dropwise, with the system temperature controlled below 35 °C during the addition process. After the addition was complete, the temperature was raised to 55 °C and maintained for 7 h. After the reaction was complete, the temperature was lowered to 25 °C, and 300 mL of purified water was added. The aqueous phase was discarded, and the organic phase was evaporated to dryness to obtain compound 3a, which had an optical purity of 100%. Based on the separation and filtration of compound 2a obtained in step (1), the separation yield of compound 3a was 31%.

[0107] Therefore, the overall yield of S-citalopram (compound 3a) prepared from racemic diol (compound 1) = resolution yield + configuration conversion yield = 31% + 51% = 82%.

[0108] Example 2

[0109] The difference between this embodiment and Embodiment 1 is that:

[0110] In step (1), D-dibenzoyl tartaric acid was replaced with D-dibenzoyl tartaric acid, and the reaction was carried out at 25°C for 12 hours until complete.

[0111] In step (1) of this embodiment, the separation yield of compound 2a is 30%.

[0112] Example 3

[0113] The difference between this embodiment and Embodiment 1 is that:

[0114] In step (1), D-diethyl tartrate is used to replace D-benzoyl tartrate, and the reaction is completed at 25°C for 10 hours.

[0115] In step (1) of this embodiment, the separation yield of compound 2a is 31%.

[0116] Example 4

[0117] The difference between this embodiment and Embodiment 1 is that:

[0118] In step (2), L-dibenzoyl tartaric acid was replaced with L-dibenzoyl tartaric acid, and the reaction was completed at 25°C for 6 hours.

[0119] In step (2) of this embodiment, the separation yield of compound 2b is 93%.

[0120] Example 5

[0121] The difference between this embodiment and Embodiment 1 is that:

[0122] In step (2), L-dibenzoyl tartaric acid is replaced with diethyl L-tartrate, and the reaction is completed at 25°C for 8 hours.

[0123] In step (2) of this embodiment, the separation yield of compound 2b is 87%.

[0124] Example 6

[0125] The difference between this embodiment and Embodiment 1 is that:

[0126] In step (3), hydrobromic acid is used to replace benzenesulfonic acid. Under the action of the sterically hindered ligand 18-crown-6, the reaction is carried out at 50°C for 5 hours to obtain a mixture of compound 3a and compound 3b.

[0127] In step (3) of this embodiment, the optical purity of the mixture is shown in Figure 6, wherein the optical purity of compound 3a is 97.08% and the optical purity of compound 3b is 2.92%.

[0128] Example 7

[0129] The difference between this embodiment and Embodiment 1 is that:

[0130] In step (3), hydroiodic acid is used to replace benzenesulfonic acid. Under the action of the sterically hindered ligand 18-crown-6, the reaction is carried out at 50°C for 6 hours to obtain a mixture of compound 3a and compound 3b.

[0131] In step (3) of this embodiment, the mass of the mixture is 8.07 g, and the separation yield of the mixture is 85.2%. The optical purity of the mixture is shown in Figure 7, wherein the optical purity of compound 3a is 97.00%, and the optical purity of compound 3b is 3.00%.

[0132] Example 8

[0133] The difference between this embodiment and Embodiment 1 is that:

[0134] In step (3), methanesulfonic acid is used to replace benzenesulfonic acid. Under the action of the sterically hindered ligand 18-crown-6, the reaction is carried out at 50°C for 6 hours to obtain a mixture of compound 3a and compound 3b.

[0135] In step (3) of this embodiment, the mass of the mixture is 8.11 g, and the separation yield of the mixture is 85.6%. The optical purity of the mixture is shown in Figure 8, wherein the optical purity of compound 3a is 95.20%, and the optical purity of compound 3b is 4.80%.

[0136] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 49.2%.

[0137] Example 9

[0138] The difference between this embodiment and Embodiment 1 is that:

[0139] In step (3), 18-crown-6 is replaced with 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthylene, and the reaction is carried out at 50°C for 6 hours under the action of benzenesulfonic acid to obtain a mixture of compound 3a and compound 3b.

[0140] In step (3) of this embodiment, the mass of the mixture is 7.99 g, and the separation yield of the mixture is 84.3%. The optical purity of the mixture is shown in Figure 9, wherein the optical purity of compound 3a is 96.98%, and the optical purity of compound 3b is 3.02%.

[0141] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 49.7%.

[0142] Example 10

[0143] The difference between this embodiment and Embodiment 1 is that:

[0144] In step (3), 18-crown-6 is replaced with 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazole-4-yl)-1H-pyrazole. The reaction is carried out at 50°C for 6 hours under the action of benzenesulfonic acid to obtain a mixture of compounds 3a and 3b.

[0145] In step (3) of this embodiment, the mass of the mixture is 8.09 g, and the separation yield of the mixture is 85.4%. The optical purity of the mixture is shown in Figure 10, wherein the optical purity of compound 3a is 96.97%, and the optical purity of compound 3b is 3.03%.

[0146] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 50.9%.

[0147] Example 11

[0148] The difference between this embodiment and Embodiment 1 is that:

[0149] In step (3), 18-crown-6 is replaced with n-butyldi(1-adamantyl)phosphine. The reaction is carried out at 50°C for 6 hours under the action of benzenesulfonic acid to obtain a mixture of compound 3a and compound 3b.

[0150] In step (3) of this embodiment, the mass of the mixture is 8.33 g, and the separation yield of the mixture is 87.9%. The optical purity of the mixture is shown in Figure 11. The optical purity of compound 3a is 96.96%, and the optical purity of compound 3b is 3.04%.

[0151] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 51.3%.

[0152] Example 12

[0153] The difference between this embodiment and Embodiment 1 is that:

[0154] In step (4), D-di-dibenzoyl tartaric acid is replaced with D-di-dibenzoyl tartaric acid, and the reaction is carried out at 60°C for 3 hours to complete the reaction.

[0155] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 51%. The optical purity of compound 3a is shown in Figure 12, wherein the optical purity of compound 3a is 99.94% and the optical purity of compound 3b is 0.06%.

[0156] Example 13

[0157] The difference between this embodiment and Embodiment 1 is that:

[0158] In step (4), D-diethyl tartrate is used to replace D-benzoyl tartrate, and the reaction is carried out at 60°C for 3 hours to complete the reaction.

[0159] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 49%. The optical purity of compound 3a is shown in Figure 13, wherein the optical purity of compound 3a is 99.82% and the optical purity of compound 3b is 0.18%.

[0160] Example 14

[0161] The difference between this embodiment and Embodiment 1 is that:

[0162] In step (4), D-dibenzoyl tartaric acid was used as the resolving agent, and anhydrous acetonitrile was used to replace anhydrous ethanol. The reaction was carried out at 60°C for 3 hours until the reaction was complete.

[0163] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 51%. The optical purity of compound 3a is shown in Figure 14, wherein the optical purity of compound 3a is 99.99% and the optical purity of compound 3b is 0.01%.

[0164] Example 15

[0165] The difference between this embodiment and Embodiment 1 is that:

[0166] In step (4), D-dibenzoyl tartaric acid was used as the resolving agent, and anhydrous acetone was used to replace anhydrous ethanol. The reaction was carried out at 50°C for 7 hours until the reaction was complete.

[0167] In step (4) of this embodiment, the configuration conversion yield of compound 3a is 46%. The optical purity of compound 3a is shown in Figure 15, wherein the optical purity of compound 3a is 99.98% and the optical purity of compound 3b is 0.02%.

[0168] Comparative Example 1

[0169] The difference between this comparative example and Example 1 is that in step (3), 20% dilute sulfuric acid was used instead of benzenesulfonic acid. A mixture of compounds 3a and 3b was obtained. The optical purity is shown in Figure 16, with compound 3a having an optical purity of 75.18% and compound 3b having an optical purity of 24.82%.

[0170] In step (4), compound 3a with high optical purity was obtained after purification. The optical purity is shown in Figure 17. The optical purity of compound 3a is 92.53%, and the optical purity of compound 3b is 7.47%.

[0171] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for preparing S-citalopram based on R-diol intermediates, characterized in that, Includes the following steps: (1) The citalopram R-diol intermediate undergoes SN2 configuration inversion under the action of sterically hindered acid and sterically hindered ligand to obtain a mixture containing S-citalopram and R-citalopram. The terrestrial barrier acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid, or hydroiodic acid. The sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1Hpyrazole or n-butylbis(1-adamantyl)phosphine; The optical purity of the citalopram R-diol intermediate is ≥80%; (2) The mixture in step (1) was subjected to the action of the resolving agent to obtain S-citalopram.

2. The method according to claim 1, characterized in that, In step (1), the steric hindrance acid is one or both of hydrobromic acid or hydroiodic acid.

3. The method according to claim 1, characterized in that, In step (1), the citalopram R-diol intermediate is obtained by resolving the racemic citalopram diol, or by resolving a mixture of the citalopram R-diol intermediate and the citalopram S-diol intermediate.

4. The method according to claim 1, characterized in that, In step (2), the resolving agent is selected from one or more of D-dibenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, or D-diethyl tartarate.

5. The method according to claim 1, characterized in that, In step (1), the reaction temperature is 40-50℃.

6. The method according to claim 1, characterized in that, In step (1), the mass ratio of the citalopram R-diol intermediate to the sterically hindered acid is 1:1.7-2.

1.

7. The method according to claim 1, characterized in that, In step (1), the molar ratio of the citalopram R-diol intermediate to the sterically hindered ligand is 1:0.05-0.

08.

8. The method according to claim 1, characterized in that, In step (2), the mass ratio of the resolving agent to the mixture in step (1) is 0.15-0.35:

10.

9. The method according to claim 1, characterized in that, In step (2), the reaction temperature is 50-60℃.

10. A method for preparing S-citalopram, characterized in that, Includes the following steps: S1. The racemic citalopram diol was separated by chiral resolution. The separated citalopram S-diol intermediate precipitated from the reaction system, and the mixture of citalopram R-diol intermediate and part of citalopram S-diol intermediate was enriched in the mother liquor of the separation. S2. The mother liquor was separated by chiral resolution to obtain citalopram R-diol intermediate; S3. In step S2, the citalopram R-diol intermediate undergoes an SN2 configuration inversion under the action of a sterically hindered acid and a sterically hindered ligand, yielding a mixture containing S-citalopram and R-citalopram. Wherein, the steric hindrance acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid; The sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphine-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1Hpyrazole or n-butylbis(1-adamantyl)phosphine; S4. The mixture in step S3 is separated by chiral resolution to obtain S-citalopram; S5. The citalopram S-diol intermediate precipitated in step S1 undergoes a ring-closing reaction to obtain S-citalopram.

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