Preparation method of S-citalopram

Abstract

The invention relates to a method for preparing S-citalopram based on an R-diol intermediate. The method comprises the following steps: (1) carrying out SN2 configuration inversion on a citalopram R-diol intermediate under the action of a large-steric-hindrance acid and a large-steric-hindrance ligand to obtain a mixture containing S-citalopram and R-citalopram; and (2) obtaining the S-citalopram from the mixture in the step (1) under the action of a resolving agent. In addition, the invention also discloses a preparation method of the S-citalopram. The optical purity of the S-citalopram prepared by the method is greater than 95%, and the optical purity is greater than 99% after the S-citalopram is purified. In addition, the total yield of S-citalopram is increased to 82% from 31% in the prior art.

Description

Technical Field

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

[0002] Escitalopram oxalate, also known as Citalopram, has a chemical name of S-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile oxalate. It is a new type of selective serotonin reuptake inhibitor jointly developed by Forest Laboratories of the United States and Lundbeck of Denmark. It was launched in the United States in August 2002 and is currently the most selective antidepressant used in clinical practice. Compared with other first-line antidepressants such as fluoxetine, venlafaxine and sertraline, this drug not only has the advantages of strong selectivity, fast treatment speed and few adverse reactions, but also has been proven in clinical trials to have outstanding performance in the treatment of depression and anxiety, making escitalopram oxalate stand out in the field of antidepressants.

[0003] Citalopram has chiral isomers. It is currently known that the antidepressant effect of the single right-handed optical isomer in the citalopram molecule, namely S-citalopram (also known as dextro-citalopram), is at least 100 times stronger than that of R-citalopram (also known as levo-citalopram). In addition, S-citalopram has higher 5-HT reuptake inhibition selectivity than racemic citalopram, has lower affinity for other receptors, has better efficacy, fewer side effects, and the dosage is also reduced by half. Therefore, S-citalopram has been widely used.

[0004] Since Citalopram went on the market, the synthesis method mainly includes: chiral resolution method, chiral source synthesis method and asymmetric catalysis method. Among them, chiral resolution method is the main method for preparing S-Citalopram in industry at present. Chiral resolution method is to use a resolving agent to split the Citalopram racemic diol intermediate (its structural formula is shown below, also known as diol), obtain Citalopram S-diol intermediate (its structure is shown below, also known as S-diol) and Citalopram R-diol intermediate (its structure is shown below, also known as R-diol), and then Citalopram S-diol intermediate is subjected to a closed-loop reaction to prepare S-Citalopram. Among them, the by-product R-diol intermediate is basically discharged in the form of waste, resulting in low atomic utilization of Citalopram, low total yield and high production cost.

[0005]

[0006] To solve the above problems, patent publication number CN101440079A discloses a method of obtaining a mixture of S-citalopram and R-citalopram by configuration flipping cyclization of a mixture of more than 50% of R-diol and S-diol under acidic conditions, wherein the highest proportion of S-citalopram (i.e., optical purity) is less than 75%. Then, the obtained configuration flipped mixture is separated from the target product (S-citalopram) by precipitation crystallization using the difference in solubility of S-citalopram and R-citalopram in different solvents. The main problems of this method are as follows: First, the proportion of more than 50% of R-diol configuration flipped to S-citalopram under acidic conditions is 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 after post-treatment is low (ee value <95%), which cannot meet the direction standards of various countries (ee>98%), and the yield after purification is low, less than 10%, which is not conducive to industrialization.

[0007] Patent publication number CN1729164A discloses a mixture of R-diol and S-diol with more than 50% enantiomers, which is converted into a mixture of S-citalopram and R-citalopram by configuration flipping, and then S-citalopram is separated through multiple recrystallization purification. The optical purity of S-citalopram separated by this method is low (ee value <95%), and the post-processing is very cumbersome, requiring multiple recrystallization purifications, resulting in a very low overall yield. Summary of the invention

[0008] In view of the above existing technical problems, the object of the present invention is to provide a method for preparing S-citalopram based on R-diol intermediate. The preparation method not only has a high configuration conversion yield, but also the prepared S-citalopram has a high optical purity.

[0009] The second object of the present invention is to provide a method for preparing S-citalopram.

[0010] The above-mentioned purpose of the present invention is achieved through the following technical solutions.

[0011] The present invention claims a method for preparing S-citalopram based on an R-diol intermediate, comprising the following steps:

[0012] (1) Citalopram R-diol intermediate undergoes SN reaction under the action of sterically hindered acid and sterically hindered ligand. 2 The configuration is flipped to obtain a mixture containing S-citalopram and R-citalopram;

[0013] The bulky hindered acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid;

[0014] The bulky sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole or n-butyldi(1-adamantyl)phosphine;

[0015] The optical purity of the Citalopram R-diol intermediate is ≥80%;

[0016] (2) The mixture treated in step (1) is subjected to the action of a resolving agent to obtain S-citalopram.

[0017] The invention provides a new method for preparing S-citalopram based on an R-diol intermediate. Under the action of a large steric hindered acid and a large steric hindered ligand, the citalopram R-diol intermediate undergoes configuration inversion cyclization to prepare S-citalopram. The ee value of S-citalopram in the obtained product is greater than 95%, which is much higher than the purity of S-citalopram in the existing method (the optical purity of S-citalopram is less than 75%). Subsequently, post-treatment is performed under the action of a resolving agent. The optical purity of the S-citalopram obtained after purification is greater than 99%, and the configuration conversion yield is greater than or equal to 46%.

[0018] Furthermore, the inventors have found through research that in the present application scheme, it is necessary to use an acid with large steric hindrance and a ligand with large steric hindrance for coordination, so as to effectively improve the efficiency of the configuration inversion cyclization and improve the optical purity of S-citalopram. The optical purity after purification can 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.

[0019] The present invention solves the problem that the currently encountered Citalopram R-diol intermediate cannot be further utilized, so that the Citalopram R-diol intermediate can be prepared by configuration conversion to obtain S-Citalopram, and its optical purity and configuration conversion yield are significantly improved. The method of the present invention solves the problems of low optical purity, low separation yield, low atomic utilization, high production cost, etc. of separating and purifying S-Citalopram.

[0020] Preferably, in step (1), the bulky hindered acid is one or both of hydrobromic acid and hydroiodic acid. Under this preference, the S-citalopram in the prepared mixture has a higher optical purity.

[0021] Preferably, in the step (1), in order to obtain a high optical purity citalopram R-diol intermediate, the citalopram diol racemate can be obtained by multiple resolution, or the mixture of the citalopram R-diol intermediate and the citalopram S-diol intermediate can be directly resolved.

[0022] Specifically, in step (1), the optical purity of the Citalopram R-diol intermediate is ≥90%. Preferably, the optical purity is ≥92%; preferably, the optical purity is ≥98%.

[0023] Specifically, the number of times of resolution using the citalopram diol racemate is ≥ 2. More specifically, in some embodiments, the citalopram diol racemate can be firstly resolved using a D-resolving agent, and then the mother liquor is resolved using an L-resolving agent to obtain a high optical purity citalopram R-diol intermediate.

[0024] Specifically, when the mixture of the citalopram R-diol intermediate and the citalopram S-diol intermediate is directly split, the splitting agent used for splitting is an L-splitting agent. More specifically, the splitting agent can be an L-splitting agent conventionally used for configuration conversion in the art. More specifically, the splitting agent is selected from one or more of L-dibenzoyltartaric acid, L-di-p-methylbenzoyltartaric acid or L-tartrate diethyl ester.

[0025] Specifically, in the mixture of citalopram R-diol intermediate and citalopram S-diol intermediate, the optical purity of citalopram R-diol intermediate is ≥40%; further preferably, the optical purity is ≥50%; more preferably, the optical purity is ≥60%; 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 an interval range formed by any of the above values, such as 50-90%, 60-99%, etc., but the present invention is not limited thereto.

[0026] 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 for configuration conversion in the art. More specifically, the resolving agent is selected from one or more of D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid or D-tartrate diethyl ester.

[0027] Preferably, in step (1), the solvent used may be one or more of toluene or ethanol.

[0028] Preferably, in step (1), the mass ratio of the citalopram R-diol intermediate to the bulky hindered acid is 1:1.7-2.1.

[0029] Preferably, in step (1), the molar ratio of the citalopram R-diol intermediate to the bulky steric ligand is 1:0.05-0.08.

[0030] Preferably, in step (1), the reaction temperature is 40-50°C.

[0031] Preferably, in step (1), the reaction time is 3-5 h.

[0032] Preferably, in step (2), the reaction temperature is 50-60°C.

[0033] Preferably, in step (2), the solvent used may be one or more of anhydrous ethanol, anhydrous acetonitrile or anhydrous acetone.

[0034] Preferably, in step (2), the mass ratio of the resolving agent to the mixture treated in step (1) is 0.15-0.35:10.

[0035] Furthermore, the present invention claims a method for preparing S-citalopram, comprising the following steps:

[0036] S1. The citalopram diol racemate is split by a chiral splitting method, and the split citalopram S-diol intermediate is precipitated from the reaction system, and a mixture of the citalopram R-diol intermediate and a portion of the citalopram S-diol intermediate is enriched in the split mother liquor;

[0037] S2. splitting the split mother liquor by a chiral splitting method to obtain a Citalopram R-diol intermediate;

[0038] S3. Step S2: The citalopram R-diol intermediate undergoes SN reaction under the action of a large sterically hindered acid and a large sterically hindered ligand. 2 The configuration is flipped to obtain a mixture containing S-citalopram and R-citalopram;

[0039] Wherein, the bulky hindered acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid;

[0040] The bulky sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole or n-butyldi(1-adamantyl)phosphine;

[0041] S4. The mixture in step S3 is split by a chiral splitting method to obtain S-citalopram;

[0042] S5. The S-diol intermediate of Citalopram precipitated in step S1 is subjected to a ring-closing reaction to obtain S-Citalopram. The reaction formula of the preparation method of S-Citalopram is shown below:

[0043]

[0044] The present invention provides a novel preparation method of S-citalopram, wherein a racemic diol intermediate is firstly split by a chiral splitting method to obtain a split mother liquor containing an R-diol intermediate; then the split mother liquor containing the R-diol intermediate is further split by a chiral splitting method to obtain an R-diol intermediate with high optical purity. Furthermore, the R-diol intermediate with high optical purity is prepared by the combined action of a large sterically hindered acid and a large sterically hindered ligand through a SN 2 The invention discloses a novel method for preparing a novel S-citalopram, wherein the configuration flips and cyclizes to form S-citalopram, and the optical purity of the obtained S-citalopram is greater than 95%, thereby solving the technical problem that the optical purity of R-diol in the existing method is insufficient (less than 75%). Furthermore, the obtained S-citalopram is further decomposed to obtain S-citalopram with an optical purity greater than 99%. Finally, the S-diol intermediate precipitated in step S1 is subjected to a ring-closing reaction to obtain S-citalopram.

[0045] The total yield of S-citalopram (step S4+step S5) obtained by the method of the present invention is higher than 75%, and can be increased to 82% at the highest.

[0046] The method of the present invention solves the problems encountered currently in the conversion of high optical purity R-diol intermediates into S-citalopram, such as low optical purity (less than 75%), low optical purity of S-citalopram after purification (ee < 95%), and low separation yield. The method of the present invention can greatly promote industrial upgrading and significantly reduce the production cost of the entire citalopram.

[0047] More specifically, in some more specific embodiments, the present invention claims a method for preparing S-citalopram, comprising the following steps:

[0048] S1. The citalopram diol racemate, the resolving agent and the solvent are mixed, and the resolved citalopram S-diol intermediate is precipitated from the reaction system, and the mixture of the citalopram R-diol intermediate and a part of the citalopram S-diol intermediate is enriched in the resolution mother liquor;

[0049] S2. The split mother liquor, splitting agent and solvent of step S1 are mixed to obtain a Citalopram R-diol intermediate;

[0050] Step S3. The citalopram R-diol intermediate, the bulky hindered acid and the bulky hindered ligand are mixed and reacted to produce SN 2 The configuration is flipped to obtain a mixture containing S-citalopram and R-citalopram;

[0051] S4. The mixture, the resolving agent and the solvent in step S3 are mixed to obtain S-citalopram;

[0052] Wherein, the bulky hindered acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid;

[0053] The bulky sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole or n-butyldi(1-adamantyl)phosphine;

[0054] S5. The S-diol intermediate of citalopram precipitated in step S1, an acyl chloride reagent, a base and a solvent are mixed to carry out a ring-closing reaction to obtain S-citalopram.

[0055] Preferably, in step S1, the resolving agent can be a D-resolving agent conventionally used for configuration conversion in the art. More specifically, the resolving agent is selected from one or more of D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid and D-diethyl tartrate.

[0056] Preferably, in step S1, the solvent is isopropanol, the reaction temperature is 20-30° C., and the reaction time is 10-12 h.

[0057] Preferably, in step S1, the mass ratio of the resolving agent to the citalopram racemic diol intermediate is 0.25-0.35:10.

[0058] Preferably, in step S2, the resolving agent can be an L-resolving agent conventionally used for configuration conversion in the art. More specifically, the resolving agent is selected from one or more of L-dibenzoyltartaric acid, L-di-p-methylbenzoyltartaric acid or L-tartrate diethyl ester.

[0059] Preferably, in step S2, the solvent is one or more of ethanol, isopropanol or dioxane.

[0060] Preferably, in step S2, the reaction time is 6-8 hours.

[0061] Preferably, in step S2, the reaction temperature is 20-30°C.

[0062] Preferably, in step S2, the mass ratio of the resolving agent to the mixture is 0.18-0.25:1.

[0063] Preferably, in step S3, the solvent is one or more of toluene or ethanol.

[0064] Preferably, in step S3, the mass ratio of the citalopram R-diol intermediate to the bulky hindered acid is 1:1.7-2.1.

[0065] Preferably, in step S3, the molar ratio of the citalopram R-diol intermediate to the bulky steric ligand is 1:0.05-0.08.

[0066] Preferably, in step S3, the reaction temperature is 40-50°C.

[0067] Preferably, in step S3, the reaction time is 3-5 hours.

[0068] Preferably, in step S4, the reaction temperature is 50-60°C.

[0069] Preferably, in step S4, the reaction solvent is one or more of anhydrous ethanol, anhydrous acetonitrile or anhydrous acetone.

[0070] 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.

[0071] Preferably, in step S4, the resolving agent can be a D-resolving agent conventionally used for configuration conversion in the art. More specifically, the resolving agent is selected from one or more of D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid and D-diethyl tartrate.

[0072] Preferably, in step S5, the acyl chloride reagent is selected from one or more of p-toluenesulfonyl chloride and acetyl chloride.

[0073] Preferably, in step S5, the base is selected from one or more of ammonia, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, methylamine, diisopropylethylamine or pyridine.

[0074] Preferably, in step S5, the solvent is toluene.

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] (1) The present invention provides a new method for preparing S-citalopram based on an R-diol intermediate. Under the action of a bulky hindered acid and a bulky hindered ligand, the citalopram R-diol intermediate undergoes configuration inversion cyclization to prepare S-citalopram. In the obtained product, the optical purity of S-citalopram is greater than 95%, which solves the technical problem of insufficient configuration conversion rate (less than 75%) of S-citalopram in the existing method. In addition, the optical purity of the S-citalopram obtained after purification is greater than 99%, which meets the standards of various countries.

[0077] (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 the highest; and the optical purity of the prepared S-citalopram is greater than 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 It is the optical purity of compound 2b in step (2) of Example 1.

[0079] Figure 2 It is the optical purity of the mixture of compound 3a and compound 3b in step (3) of Example 1.

[0080] Figure 3 This is the H NMR spectrum of compound 3a in step (3) of Example 1.

[0081] Figure 4 This is the NMR carbon spectrum of compound 3a in step (3) of Example 1.

[0082] Figure 5 It is the optical purity of compound 3a obtained after purification in step (4) of Example 1.

[0083] Figure 6 The optical purity of compound 3 was obtained by replacing benzenesulfonic acid with hydrobromic acid and using 18-crown-6 as the ligand.

[0084] Figure 7 The optical purity of compound 3 was obtained by replacing benzenesulfonic acid with hydroiodic acid and using 18-crown-6 as the ligand.

[0085] Figure 8 The optical purity of compound 3 was obtained by replacing benzenesulfonic acid with methanesulfonic acid and using 18-crown-6 as the ligand.

[0086] Fig. 9 Replacing 18-crown-6 with 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl gave compound 3 of optical purity.

[0087] Fig.10 The optical purity of compound 3 was obtained by replacing 18-crown-6 with 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole.

[0088] Fig.11 The optical purity of compound 3 was obtained by replacing 18-crown-6 with n-butyldi(1-adamantyl)phosphine.

[0089] Fig.12 The optical purity of compound 3a was obtained by replacing D-di-p-toluoyltartaric acid with D-di-p-toluoyltartaric acid.

[0090] Fig.13 The optical purity of compound 3a was obtained by replacing D-dibenzoyltartaric acid with D-diethyl tartarate.

[0091] Fig.14 Using D-dibenzoyltartaric acid as the resolving agent and anhydrous acetonitrile instead of anhydrous ethanol, the optical purity of the obtained compound 3a was

[0092] Fig.15 Using D-dibenzoyltartaric acid as the resolving agent and anhydrous acetone instead of anhydrous ethanol, the optical purity of the obtained compound 3a was

[0093] Fig.16 By using dilute sulfuric acid instead of benzenesulfonic acid, an optically pure mixture of compound 3a and compound 3b was obtained.

[0094] Fig.17 The optical purity of compound 3a obtained after purification was obtained by using dilute sulfuric acid instead of benzenesulfonic acid. DETAILED DESCRIPTION

[0095] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present invention. However, those skilled in the art will appreciate that the present invention can be implemented without using these details. The description of multiple embodiments hereinafter is made with the understanding that the present disclosure is to be regarded as an example of the subject matter claimed for protection, rather than being intended to limit the appended claims to the specific embodiments described. The titles used throughout the full text of the present disclosure are merely for convenience and are not to be interpreted as limiting the claims in any way. The embodiments described under any title may be combined with the embodiments described under any other title.

[0096] Example 1 Preparation of S-Citalopram

[0097] The reaction formula and reaction steps are shown below:

[0098]

[0099] (1) Synthesis of compounds 2a and 2b

[0100] At room temperature, 10 g of compound 1, 310 mg of resolving agent D-dibenzoyltartaric acid, and 120 mL of isopropanol were added to a 500 mL three-necked flask, and the reaction was kept at 25 ° C for 11 hours. After the reaction was completed, the compound 2a (S-diol) was obtained by suction filtration. The separation yield of compound 2a was 35% based on compound 1. The mother liquor remaining after the split (the mother liquor was 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 reduced and evaporated to dryness for standby use.

[0101] (2) Synthesis of compound 2b

[0102] Add 110 mL of ethanol to the reduced-evaporation substrate of step (1), slowly add 160 mg of the resolving agent L-dibenzoyltartaric acid, and keep the reaction at 25° C. for 7 hours. After the reaction is completed, directly filter to obtain high optical purity R-diol (i.e., compound 2b), and dry the crude product for standby use. Calculated based on the citalopram R-diol intermediate of step (1), the separation yield of compound 2b is 91%; Figure 1 As shown, the optical purity of R-diol was 92.39%.

[0103] (3) Synthesis of a mixture of compound 3a and compound 3b

[0104] At room temperature, 10 g of compound 2b, 150 mL of toluene, 21 g of benzenesulfonic acid and 220 mg of the large steric ligand 18-crown-6 were added to a 250 mL three-necked flask in sequence, and the temperature of the reaction system was raised to 45 ° C and kept for 4 hours. 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 compound 3a and compound 3b. The mass of the mixture was 8.23 ​​g. Calculated based on compound 2b, the separation yield of the mixture was 86.9%. The optical purity was as follows Figure 2 As shown, the optical purity of compound 3a was 95.48%, and the optical purity of compound 3b was 4.52%.

[0105] (4) Purification of compound 3a

[0106] Add 20g of a mixture of compound 3a and compound 3b to a 500mL reaction bottle at room temperature, add 300mL of anhydrous ethanol, and stir at room temperature for 10min. Add 330mg of the resolving agent D-dibenzoyltartaric acid, raise the temperature to 55°C, and keep the reaction for 2.5h. After the reaction is completed, cool to -15°C, keep the reaction for 1h, filter, and dry the filter cake to obtain 10.2g of high optical purity compound 3a. Calculated on the mixture, the configuration conversion yield of compound 3a is 51%. The NMR hydrogen spectrum and NMR carbon spectrum of compound 3a are shown in Figure 3 and Figure 4 The optical purity is shown as Figure 5As shown, the optical purity of compound 3a was 99.92%, and the optical purity of compound 3b was 0.08%.

[0107] (5) Synthesis of compound 3a

[0108] At room temperature, compound 2a obtained by separation and filtration in step (1), 3.6 g of triethylamine and 100 mL of toluene were added to a 500 mL reaction bottle in sequence, and p-toluenesulfonyl chloride was slowly added dropwise. The temperature of the system was controlled to be less than 35°C during the addition process. After the addition was completed, the temperature was raised to 55°C and the reaction was kept warm for 7 hours. After the reaction was completed, the temperature was lowered to 25°C, 300 mL of purified water was added to separate, the aqueous phase was discarded, and the organic phase was evaporated to dryness to obtain compound 3a. The optical purity of compound 3a was 100%. Based on compound 2a obtained by separation and filtration in step (1), the separation yield of compound 3a was 31%.

[0109] Therefore, the total yield of S-citalopram (Compound 3a) prepared from racemic diol (Compound 1) = resolution yield + configuration conversion yield = 31% + 51% = 82%.

[0110] Example 2

[0111] The difference between this embodiment and embodiment 1 is that:

[0112] In step (1), D-di-p-methylbenzoyltartaric acid is used to replace D-dibenzoyltartaric acid, and the reaction is completed at 25° C. for 12 hours.

[0113] In step (1) of this example, the isolated yield of compound 2a is 30%.

[0114] Example 3

[0115] The difference between this embodiment and embodiment 1 is that:

[0116] In step (1), D-diethyl tartrate is used to replace D-dibenzoyltartaric acid, and the reaction is completed at 25° C. for 10 h.

[0117] In step (1) of this example, the isolated yield of compound 2a is 31%.

[0118] Example 4

[0119] The difference between this embodiment and embodiment 1 is that:

[0120] In step (2), L-di-p-methylbenzoyltartaric acid is used to replace L-dibenzoyltartaric acid, and the reaction is completed at 25° C. for 6 hours.

[0121] In step (2) of this example, the isolated yield of compound 2b is 93%.

[0122] Example 5

[0123] The difference between this embodiment and embodiment 1 is that:

[0124] In step (2), L-diethyl tartarate is used to replace L-dibenzoyltartaric acid, and the reaction is completed at 25° C. for 8 hours.

[0125] In step (2) of this example, the isolated yield of compound 2b is 87%.

[0126] Example 6

[0127] The difference between this embodiment and embodiment 1 is that:

[0128] In step (3), hydrobromic acid is used to replace benzenesulfonic acid, and the reaction is completed at 50° C. for 5 h under the action of the bulky steric ligand 18-crown-6 to obtain a mixture of compound 3a and compound 3b.

[0129] In step (3) of this embodiment, the optical purity of the mixture is as follows Figure 6 As shown, the optical purity of compound 3a is 97.08%, and the optical purity of compound 3b is 2.92%.

[0130] Example 7

[0131] The difference between this embodiment and embodiment 1 is that:

[0132] In step (3), hydroiodic acid is used to replace benzenesulfonic acid, and the reaction is completed at 50° C. for 6 h under the action of the bulky steric ligand 18-crown-6 to obtain a mixture of compound 3a and compound 3b.

[0133] 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 as follows: Figure 7 As shown, the optical purity of compound 3a is 97.00%, and the optical purity of compound 3b is 3.00%.

[0134] Example 8

[0135] The difference between this embodiment and embodiment 1 is that:

[0136] In step (3), methanesulfonic acid is used instead of benzenesulfonic acid, and the reaction is completed at 50° C. for 6 h under the action of the bulky steric ligand 18-crown-6 to obtain a mixture of compound 3a and compound 3b.

[0137] 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 as follows: Figure 8As shown, the optical purity of compound 3a is 95.20%, and the optical purity of compound 3b is 4.80%.

[0138] In step (4) of this example, the configuration conversion yield of compound 3a is 49.2%.

[0139] Example 9

[0140] The difference between this embodiment and embodiment 1 is that:

[0141] In step (3), 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl is used to replace 18-crown-6, and the reaction is completed at 50°C for 6 hours under the action of benzenesulfonic acid to obtain a mixture of compound 3a and compound 3b.

[0142] 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 as follows: Fig. 9 As shown, the optical purity of compound 3a is 96.98%, and the optical purity of compound 3b is 3.02%.

[0143] In step (4) of this example, the configuration conversion yield of compound 3a is 49.7%.

[0144] Example 10

[0145] The difference between this embodiment and embodiment 1 is that:

[0146] In step (3), 5-(di-tert-butylphosphine)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole is used to replace 18-crown-6, and the reaction is completed at 50°C for 6 hours under the action of benzenesulfonic acid to obtain a mixture of compound 3a and compound 3b.

[0147] 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 as follows: Fig.10 As shown, the optical purity of compound 3a is 96.97%, and the optical purity of compound 3b is 3.03%.

[0148] In step (4) of this example, the configuration conversion yield of compound 3a was 50.9%.

[0149] Embodiment 11

[0150] The difference between this embodiment and embodiment 1 is that:

[0151] In step (3), n-butyl di(1-adamantyl)phosphine is used to replace 18-crown-6, and the reaction is completed at 50° C. for 6 h under the action of benzenesulfonic acid to obtain a mixture of compound 3a and compound 3b.

[0152] 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 as follows: Fig.11 As shown, the optical purity of compound 3a was 96.96%, and the optical purity of compound 3b was 3.04%.

[0153] In step (4) of this example, the configuration conversion yield of compound 3a was 51.3%.

[0154] Example 12

[0155] The difference between this embodiment and embodiment 1 is that:

[0156] In step (4), D-di-p-methylbenzoyltartaric acid is used to replace D-dibenzoyltartaric acid, and the reaction is completed at 60° C. for 3 h.

[0157] In step (4) of this example, the configuration conversion yield of compound 3a was 51%. The optical purity of compound 3a is as follows Fig.12 As shown, the optical purity of compound 3a is 99.94%, and the optical purity of compound 3b is 0.06%.

[0158] Example 13

[0159] The difference between this embodiment and embodiment 1 is that:

[0160] In step (4), D-diethyl tartrate is used to replace D-dibenzoyltartaric acid, and the reaction is completed at 60° C. for 3 h.

[0161] In step (4) of this example, the configuration conversion yield of compound 3a was 49%. The optical purity of compound 3a is as follows Fig.13 As shown, the optical purity of compound 3a is 99.82%, and the optical purity of compound 3b is 0.18%.

[0162] Embodiment 14

[0163] The difference between this embodiment and embodiment 1 is that:

[0164] In step (4), D-dibenzoyltartaric acid is used as a resolving agent, anhydrous acetonitrile is used to replace anhydrous ethanol, and the reaction is carried out at 60° C. for 3 h to complete the reaction.

[0165] In step (4) of this example, the configuration conversion yield of compound 3a was 51%. The optical purity of compound 3a is as follows Fig.14As shown, the optical purity of compound 3a is 99.99%, and the optical purity of compound 3b is 0.01%.

[0166] Embodiment 15

[0167] The difference between this embodiment and embodiment 1 is that:

[0168] In step (4), D-dibenzoyltartaric acid is used as a resolving agent, anhydrous acetone is used to replace anhydrous ethanol, and the reaction is carried out at 50° C. for 7 hours to complete the reaction.

[0169] In step (4) of this example, the configuration conversion yield of compound 3a is 46%. The optical purity of compound 3a is as follows Fig.15 As shown, the optical purity of compound 3a is 99.98%, and the optical purity of compound 3b is 0.02%.

[0170] Comparative Example 1

[0171] The difference between this comparative example and Example 1 is that in step (3), 20% dilute sulfuric acid is used instead of benzenesulfonic acid. A mixture of compound 3a and compound 3b is obtained. The optical purity is as follows: Fig.16 As shown, the optical purity of compound 3a was 75.18%, and the optical purity of compound 3b was 24.82%.

[0172] In step (4), after purification, compound 3a with high optical purity is obtained. Fig.17 As shown, the optical purity of compound 3a is 92.53%, and the optical purity of compound 3b is 7.47%.

[0173] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

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

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

3. The method according to claim 1, characterized in that: In the step (1), the citalopram R-diol intermediate is obtained by resolving the citalopram diol racemate, 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 the step (2), the resolving agent is selected from one or more of D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid or D-diethyl tartrate.

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

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

1.

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

08.

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

10.

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

10. A method for preparing S-citalopram, characterized in that: The following steps are involved: S1. The citalopram diol racemate is split by a chiral splitting method, and the split citalopram S-diol intermediate is precipitated from the reaction system, and a mixture of the citalopram R-diol intermediate and a portion of the citalopram S-diol intermediate is enriched in the split mother liquor; S2. splitting the split mother liquor by a chiral splitting method to obtain a Citalopram R-diol intermediate; S3. In step S2, the citalopram R-diol intermediate undergoes SN2 configuration inversion under the action of a large steric hindered acid and a large steric hindered ligand to obtain a mixture containing S-citalopram and R-citalopram; Wherein, the bulky hindered acid is one or more of methanesulfonic acid, benzenesulfonic acid, hydrobromic acid or hydroiodic acid; The bulky sterically hindered ligand is one or more of 18-crown-6, 2-di-tert-butylphosphino-2'-isopropoxy-1,1'-binaphthyl, 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole or n-butyldi(1-adamantyl)phosphine; S4. The mixture in step S3 is split by a chiral splitting method to obtain S-citalopram; S5. The S-citalopram diol intermediate precipitated in step S1 is subjected to a ring-closing reaction to obtain S-citalopram.

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