Preparation method of doxylamine succinate

Abstract

The invention discloses a preparation method of doxylamine succinate, which comprises the following steps: by taking 1-phenyl-1-(pyridine-2-yl) 1-ethanol and ethylene carbonate as raw materials, dissolving the 1-phenyl-1-(pyridine-2-yl) 1-ethanol and the ethylene carbonate in an organic solvent under the protection of nitrogen or inert gas, and carrying out substitution reaction under the action of an alkali reagent to obtain the doxylamine succinate. In the presence of an acid-binding agent and a catalyst, adding a sulfonyl chloride compound for reaction, and finally adding a dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride for substitution reaction; and after the reaction is finished, carrying out post-treatment to obtain doxylamine. Doxylamine and succinic acid are subjected to a salt forming reaction in a reaction solvent, and doxylamine succinate is obtained. The method is short in route, mild in reaction condition and easy and convenient to operate, and in the whole reaction process, safety is high, cost is low, stability is good, and aftertreatment is simple; the total yield reaches 95% or above, and the purity reaches 99.8% or above.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis and relates to a preparation method of doxylamine succinate. Background Art

[0002] Doxylamine succinate is an ethanolamine antihistamine drug with antihistamine, anticholinergic and significant sedative and hypnotic effects. It has strong activity and low gastrointestinal side effects, and is suitable for the short-term treatment of various allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis and insomnia. In October 1978, the FDA approved the marketing of doxylamine succinate 25mg tablets of CHATTEM company for helping with difficulty falling asleep. On April 8, 2013, the FDA approved the oral sustained-release tablets of doxylamine succinate and pyridoxine hydrochloride (trade name: Diclegis) for the treatment of nausea and vomiting in pregnant women who do not respond well to conservative treatment.

[0003] The existing chemical synthesis routes of doxylamine succinate mostly use 2-acetylpyridine as the starting material, react with the Grignard reagent prepared from iodobenzene or bromobenzene to generate the important intermediate 2-pyridylphenylmethanol, and then 2-pyridylphenylmethanol reacts with 2-dimethylaminoethyl chloride under the action of an organic base to generate doxylamine (chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine), and finally forms a salt with succinic acid to obtain doxylamine succinate. The preparation methods of doxylamine succinate mainly include the following several:

[0004] Method 1: Using pyridine and acetophenone as the starting materials, the specific route is as follows:

[0005]

[0006] The first step of this reaction route is a condensation reaction, using metallic aluminum or magnesium alloy and highly toxic mercury and mercuric chloride as catalysts, with low reaction efficiency and yield, complex post-treatment, and difficulty in industrialization; 2-chloroethyl dimethylamine in the second step is a controlled product, expensive, and not easy to store. In addition, metallic sodium is used as a hydrogen abstraction reagent, and hydrogen gas will be generated during the reaction, which is relatively dangerous to apply and not suitable for large-scale production operation. The yield of the free base prepared by this method is only 75%.

[0007] Method 2: Using bromobenzene and 2-acetylpyridine as the starting materials, the specific route is as follows:

[0008]

[0009] The first step of this reaction route involves a hazardous Grignard reaction with ether, which is flammable and explosive, as the solvent. Moreover, 2-pyridylphenylmethyl alcohol needs to be purified by distillation, with low reaction efficiency, complex post-treatment. The melting point of 2-pyridylphenylmethyl alcohol is 33 - 34.5 °C, and it is difficult to ensure the product yield and purity during distillation, making industrialization difficult, and toxic benzene by-products will be generated. In the second step, 2-chloroethyl dimethylamine is a controlled product, expensive, and not easy to store. Its boiling point is 109 - 110 °C. If toluene (boiling point 110.6 °C) is used as the reaction solvent, the two will form an azeotrope, resulting in the conversion rate of doxylamine being reduced due to the volatilization of 2-chloroethyl dimethylamine, and it is necessary to use an excess or add materials in batches, increasing the cost. If xylene (boiling point 138.4 - 144.4 °C) is used, the conversion rate of doxylamine will also be reduced due to the volatilization of 2-chloroethyl dimethylamine. In addition, when sodium amide is used as the hydrogen abstraction reagent, ammonia gas will be generated during the reaction, which is relatively dangerous to apply and not suitable for large-scale production operations. Moreover, doxylamine needs to be separated and purified by column chromatography, and this purification method is difficult for industrialization. The yield of the free base is only 46%. In CN102108059A, salification requires freezing at -20 °C for 24 hours, with high energy consumption and difficult to achieve industrial production. The yield of the final product is low, and the total yield is about 31%.

[0010] Method 3: Using 2-acetylpyridine as the starting material, the specific route is as follows:

[0011]

[0012] This reaction route is similar to Method 2. The first step involves a hazardous Grignard reaction with ether, which is flammable and explosive, as the solvent, and has complex post-treatment and difficulty in industrialization. In addition, toxic benzene by-products will be generated. In the second step, 2-chloroethyl dimethylamine is a controlled product, expensive, and not easy to store. Its boiling point is 109 - 110 °C. When xylene is used as the reaction solvent, the conversion rate of doxylamine will be reduced due to the volatilization of 2-chloroethyl dimethylamine. In addition, when sodium amide is used as the hydrogen abstraction reagent, ammonia gas will be generated during the reaction, which is relatively dangerous to apply and not suitable for large-scale production operations. Moreover, doxylamine needs to be separated and purified by column chromatography, and this purification method is difficult for industrialization. The crude succinate doxylamine is recrystallized twice with acetone, resulting in a low yield of the final product.

[0013] Method 4: Using 2-acetylpyridine as the starting material, the specific route is as follows:

[0014]

[0015] The first step of this reaction route is similar to the first step of Method 2. It also involves a dangerous Grignard reaction. 2-Pyridylphenylmethyl alcohol needs to be purified by distillation. The reaction efficiency is low, the post-treatment is complex, and it is difficult to ensure the yield and purity of 2-pyridylphenylmethyl alcohol by distillation. It is difficult to industrialize and will produce toxic benzene by-products. In the second step, the reaction time between 2-pyridylphenylmethyl alcohol and 2-chloroethyl dimethylamine hydrochloride is long (72 h). 2-Chloroethyl dimethylamine hydrochloride is a controlled product, expensive, and not easy to store. 2-Chloroethyl dimethylamine hydrochloride will azeotrope with the reaction solvent toluene, causing 2-chloroethyl dimethylamine to volatilize and reduce the conversion rate of doxylamine. It is necessary to overdose or feed in batches, increasing the cost. The yield of the second step is relatively low, about 70-80%.

[0016] Method 5: Using acetophenone and 2-bromopyridine as starting materials, the specific route is as follows:

[0017]

[0018] In the first step of this reaction route, n-butyllithium is used. n-Butyllithium will ignite spontaneously when encountering water and is extremely flammable. The reaction solvent is flammable and explosive ethers (such as diethyl ether), which is not suitable for operation in large-scale production. In the second step, 2-chloroethyl dimethylamine is a controlled product, expensive, and not easy to store. If toluene is used, 2-chloroethyl dimethylamine will azeotrope with toluene, causing 2-chloroethyl dimethylamine to volatilize and reduce the conversion rate of doxylamine. It is necessary to overdose or feed in batches, increasing the cost. If xylene is used as the reaction solvent during reflux reaction, it will also cause 2-chloroethyl dimethylamine to volatilize and reduce the conversion rate of doxylamine. In addition, using sodium amide as a hydrogen abstraction reagent will generate ammonia gas during the reaction, which is relatively dangerous for large-scale application and not suitable for large-scale production operation.

[0019] Method 6: Using 2-benzoylpyridine as the starting material, the specific route is as follows:

[0020]

[0021] The first step of this reaction route involves a dangerous Grignard reaction. The solvent is flammable and explosive diethyl ether, and 2-pyridylphenylmethyl alcohol needs to be purified by column chromatography. The post-treatment is complex and it is difficult to industrialize. In the second step, 2-chloroethyl dimethylamine is a controlled product, expensive, and not easy to store. It will azeotrope with the reaction solvent toluene, causing 2-chloroethyl dimethylamine to volatilize and reduce the conversion rate of doxylamine. It is necessary to overdose or feed in batches, increasing the cost. In addition, using sodium hydride as a hydrogen abstraction reagent will generate hydrogen gas during the reaction, which is relatively dangerous for application and not suitable for large-scale production operation. Moreover, doxylamine needs to be separated and purified by column chromatography, and this purification method is difficult to industrialize. The yield of the final product is relatively low.

[0022] Method 7: Using 2-pyridylphenylmethanol as the starting material, the specific route is as follows:

[0023]

[0024] Although this method has fewer steps, 2-chloroethyl dimethylamine is a controlled substance and is not easy to store. Using xylene as the reaction solvent and refluxing under nitrogen protection will cause the conversion rate of doxylamine to decrease due to the violent volatilization of 2-chloroethyl dimethylamine, and a large excess of feed is required, increasing the cost. In addition, using sodium amide as the hydrogen abstraction reagent will generate ammonia gas during the reaction, and its large-scale application is relatively dangerous and not suitable for large-scale production operations.

[0025] In summary, the synthetic route of doxylamine succinate has the following deficiencies:

[0026] 1. When preparing 2-pyridylphenylmethanol, in Method 1, highly toxic mercury and mercuric chloride are used as catalysts and metallic sodium is used as the hydrogen abstraction reagent; in Methods 2, 3, 4, and 6, self-made Grignard reagents are used, which are highly dangerous, have complex post-treatment, and are difficult to industrialize. Especially in Methods 2, 3, and 4, toxic benzene by-products will be generated; in Method 5, n-butyllithium is used, which will spontaneously ignite when encountering water and is extremely flammable, and the solvent is flammable and explosive ether, which is not suitable for operation in large-scale production;

[0027] 2. When preparing doxylamine free base, controlled substance 2-chloroethyl dimethylamine or its hydrochloride is used as the raw material, which is expensive and not easy to store. When using toluene as the reaction solvent, 2-chloroethyl dimethylamine and toluene will form an azeotrope, resulting in the conversion rate of doxylamine decreasing due to the volatilization of 2-chloroethyl dimethylamine. When using xylene as the reaction solvent, the same problem will occur, and an excess or batch feeding is required, greatly increasing the cost; when preparing doxylamine free base, metal sodium, sodium amide or sodium hydride hydrogen abstraction reagents are needed, which are super strong bases and will react violently and rapidly with water, easily causing spraying, explosion and other dangers, not suitable for large-scale production operations, and the reaction time is long, and the free base doxylamine needs to be separated and purified by column chromatography, making industrialization difficult;

[0028] 3. Although Method 7 has made great technical improvements and directly uses 2-pyridylphenylmethanol as the raw material to prepare the product through two-step reactions, the excessive use of 2-chloroethyl dimethylamine and the explosive, operationally dangerous and difficult-to-industrialize sodium amide cannot be avoided during the preparation of doxylamine free base; especially when adjusting the pH of the reaction, it is a reflux reaction in xylene, and the boiling point of xylene is much higher than that of 2-chloroethyl dimethylamine, resulting in increased cost and decreased conversion rate.

[0029] It can be seen that the current chemical synthesis technology of doxylamine succinate has many deficiencies such as low yield, cumbersome post-treatment, high cost, high toxicity, safety hazards, and inability to carry out large-scale industrial production. Therefore, it is of great significance to develop a new synthesis process to improve the yield, simplify the operation steps, reduce the cost, and develop a doxylamine succinate process suitable for large-scale industrial production. Summary of the Invention

[0030] The purpose of the present invention is to provide a preparation method of doxylamine succinate.

[0031] The technical solution of the present invention is as follows:

[0032] A preparation method of doxylamine succinate, the synthesis route is as follows:

[0033]

[0034] Including:

[0035] Step 1: Using 1-phenyl-1-(pyridin-2-yl)ethanol (Compound 2) and ethylene carbonate as raw materials, under the protection of nitrogen or inert gas, dissolve 1-phenyl-1-(pyridin-2-yl)ethanol and ethylene carbonate in an organic solvent, and carry out a substitution reaction under the action of a base reagent. In the presence of an acid-binding agent and a catalyst, then add a sulfonyl chloride compound for reaction, and finally add a dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride for a substitution reaction; after the reaction is completed, carry out post-treatment to obtain doxylamine (Compound 3, chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine);

[0036] Step 2: Doxylamine reacts with succinic acid in a reaction solvent to form a salt, obtaining doxylamine succinate (Compound 1, chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridyl)ethoxy]ethylamine succinate).

[0037] In Step 1, the molar ratio of 1-phenyl-1-(pyridin-2-yl)ethanol to ethylene carbonate is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.15.

[0038] The mass-volume ratio of 1-phenyl-1-(pyridin-2-yl)ethanol to the organic solvent is 1:1 to 1:20 g / mL, preferably 1:2 to 1:10 g / mL, and more preferably 1:4 to 1:8 g / mL.

[0039] The organic solvent is selected from one or more of solvents such as tetrahydrofuran, methyltetrahydrofuran, dioxane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc.

[0040] The molar ratio of the described 1-phenyl-1-(pyridin-2-yl)ethanol to the base reagent is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.15.

[0041] The described base reagent is selected from at least one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium isopropoxide, potassium isopropoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, N,N-diisopropylethylamine, etc.

[0042] The molar ratio of the described 1-phenyl-1-(pyridin-2-yl)ethanol to the catalyst is 1:1 to 1:1.5, preferably 1:1.05 to 1:1.15.

[0043] The described catalyst is 4-dimethylaminopyridine (DMAP).

[0044] The molar ratio of the described acid-binding agent to 4-dimethylaminopyridine is 3:1 to 3.5:1.

[0045] The described acid-binding agent is triethylamine.

[0046] The molar ratio of the described 1-phenyl-1-(pyridin-2-yl)ethanol to the sulfonyl chloride compound is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.15.

[0047] The described sulfonyl chloride compound is methanesulfonyl chloride or p-toluenesulfonyl chloride.

[0048] Preferably, the temperature of the substitution reaction between 1-phenyl-1-(pyridin-2-yl)ethanol (Compound 2) and ethylene carbonate is 30 to 150 °C, and the reaction time is 1 to 4 hours; after adding the sulfonyl chloride compound, the reaction temperature is 0 ± 5 °C, and the reaction time is 2 to 12 h; after adding the dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride, the substitution reaction temperature is 20 to 60 °C, and the substitution reaction time is 2 to 24 h.

[0049] More preferably, the temperature of the substitution reaction between the described 1-phenyl-1-(pyridin-2-yl)ethanol (Compound 2) and ethylene carbonate is 50 to 60 °C, and the reaction time is 1 to 4 hours; after adding the sulfonyl chloride compound, the reaction temperature is 0 ± 5 °C, and the reaction time is 2 to 5 hours; after adding the dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride, the substitution reaction temperature is 35 ± 5 °C, and the substitution reaction time is 6 to 8 hours.

[0050] The post-treatment is as follows: according to the volume ratio of the organic solvent to water being 2:1 to 1.8:1 and the volume ratio of the organic solvent to the extraction solvent being 0.9:1 to 1:1, water and the extraction solvent are added to the reaction solution, the pH value is adjusted to 3 to 4 with 6% to 10% hydrochloric acid, the organic phase is discarded, the pH value of the aqueous phase is adjusted to 8 to 9 with saturated sodium carbonate solution or saturated potassium carbonate solution, extraction is carried out with ethyl acetate or isopropyl acetate, the organic phase is retained, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine.

[0051] The extraction solvent is ethyl acetate or isopropyl acetate.

[0052] In step two, the molar ratio of doxylamine to succinic acid is 1:0.9 to 1:1.1, preferably 1:0.95 to 1:1.05, and more preferably 1:1.

[0053] The reaction solvent is selected from one or two of acetone, acetonitrile, ethyl acetate, isopropyl acetate, isopropanol, ethanol, and methanol. Preferably, it is a mixed solvent with a volume ratio of acetone to one solvent selected from ethyl acetate or acetone being 4:1 to 1:4, and more preferably a mixed solvent with a volume ratio of acetone to one solvent selected from ethyl acetate or acetone being 2:1 to 1:1.

[0054] The mass-volume ratio of doxylamine to the reaction solvent is 1:1 to 1:10 g / mL, preferably 1:2 to 1:6 g / mL, and more preferably 1:3.5 to 1:6 g / mL.

[0055] The temperature of the salt-forming reaction is -10 to 30 °C, preferably -5 to 5 °C; the time of the salt-forming reaction is 0.5 to 12 hours, preferably 5 to 6 hours.

[0056] Preferably, crystallization occurs simultaneously during the salt-forming reaction. After the crystallization ends, suction filtration and drying are carried out to obtain doxylamine succinate.

[0057] Specifically, a preparation method of doxylamine succinate includes the following steps:

[0058] Step 1: Using 1-phenyl-1-(pyridin-2-yl)ethanol and ethylene carbonate as raw materials, under the protection of nitrogen or inert gas, 1-phenyl-1-(pyridin-2-yl)ethanol and ethylene carbonate are dissolved in an organic solvent, a base reagent is added, and under the action of the base reagent, 1-phenyl-1-(pyridin-2-yl)ethanol and ethylene carbonate undergo a substitution reaction. After the reaction ends, it is cooled to room temperature, triethylamine and 4-dimethylaminopyridine are added, cooled to 0 ± 5 °C, and a sulfonyl chloride compound is added for reaction. After the reaction ends, a dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride is added for a substitution reaction; after the reaction ends, post-treatment is carried out to obtain doxylamine.

[0059] Step 2: At room temperature, dissolve doxylamine in a reaction solvent, cool it to 0±5°C, add succinic acid, and carry out a salt formation reaction. Then, perform suction filtration and drying to obtain doxylamine succinate.

[0060] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0061] The present invention provides a brand-new preparation method of doxylamine succinate, which is of great significance for the process research and process control of doxylamine succinate.

[0062] The present invention avoids the excessive use of expensive and low-boiling-point controlled products such as 2-chloroethyl dimethylamine or its hydrochloride as raw materials. Using 1-phenyl-1-(pyridin-2-yl)ethanol and ethylene carbonate as starting materials, after the reaction is completed, without post-treatment, directly react with methanesulfonyl chloride or p-toluenesulfonyl chloride, and then add dimethylamine or its hydrochloride to prepare free base of doxylamine by one-pot method, avoiding the loss of intermediates or products caused by post-treatment and improving the conversion rate of the product; in addition, the low-temperature salt formation and crystallization methods can stably reproduce the target crystal form.

[0063] The preparation method of doxylamine succinate of the present invention has a short route, mild reaction conditions, simple operation, high safety, low cost, good stability and simple post-treatment during the whole reaction process; the total yield reaches more than 95%, and the purity reaches more than 99.8%. Description of the Drawings

[0064] Figure 1 1H NMR spectrum of doxylamine succinate obtained in Example 1.

[0065] Figure 2 Liquid phase purity spectrum of doxylamine succinate obtained in Example 1.

[0066] Figure 3 DSC diagram of doxylamine succinate obtained in Example 1. Detailed Description of the Invention

[0067] The technical solutions of the present invention are further illustrated by the following examples. The examples are only used to more specifically illustrate the preferred implementation schemes of the present invention and are not used to limit the technical solutions of the present invention. Any methods and materials similar or equivalent to the content described can be used in the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0068] For the experimental methods without specific conditions indicated in the following examples, they are usually prepared according to conventional conditions.

[0069] Example 1

[0070] Step 1. Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)ethanol (Compound 2, 278.95 g, 1.4 mol), ethylene carbonate (135.61 g, 1.54 mol), sodium tert-butoxide (148.0 g, 1.54 mol) and tetrahydrofuran (2 L) were mixed and stirred to dissolve. The mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed, the system was cooled to room temperature. Triethylamine (467.5 g, 4.62 mol) and 4-dimethylaminopyridine (DMAP, 188.14 g, 1.54 mol) were added and stirred to dissolve. Then it was cooled to 0 ± 5 °C, and p-toluenesulfonyl chloride (293.6 g, 1.54 mol) was added. The reaction was carried out at 0 ± 5 °C for 3 h. Then dimethylamine hydrochloride (251.14 g, 3.08 mol) was added, and the temperature was raised to 35 ± 5 °C and reacted for 8 h. After the reaction was completed, the reaction solution was poured into 1 L of water, 2 L of ethyl acetate was added, and the mixture was stirred evenly. The pH value was adjusted to 3 with 8% hydrochloric acid, and the organic phase was discarded. The pH value of the aqueous phase was adjusted to 9 with saturated sodium carbonate solution, and then extracted with ethyl acetate. The organic phase was retained, dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain doxylamine (Compound 3, light yellow oil, 367.88 g, yield 97.19%).

[0071] Step 2. At room temperature, doxylamine (Compound 3, 350.0 g, 1.295 mol), ethyl acetate (700 mL) and acetone (1400 mL) were stirred to dissolve. The temperature was lowered to 0 ± 5 °C, and succinic acid (152.87 g, 1.295 mol) was added thereto. Crystallization was carried out by stirring at 0 ± 5 °C for 5 h, and then filtered by suction and dried to obtain doxylamine succinate (493.11 g, yield 98.06%, HPLC purity 99.96%).

[0072] 1 H NMR (600 MHz, DMSO-d6) δ: 12.57 (s, 2H, COOH), 8.48 (d, 1H, NH, J = 4.08), 7.78 (m, 1H, Ar-H), 7.62 (d, 1H, Ar-H, J = 7.98), 7.36 (d, 2H, Ar-H, J = 7.44), 7.28 (t, 2H, Ar-H, J = 7.5), 7.23 (m, 2H, Ar-H), 3.38 (m, 2H, -CH 2 ),2.68 (m, 2H, -CH 2 ),2.38 (s, 4H, -CH 2 ),2.30 (s, 6H, -CH 3 ),1.91 (s, 3H, -CH 3 ).

[0073] The DSC pattern of doxylamine succinate is shown in Figure 3, there is a sharp endothermic peak at around 105.70 °C to 107.52 °C, which is consistent with the doxylamine succinate polymorph A in CN105218433A.

[0074] Example 2

[0075] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)ethanol (Compound 2, 278.95 g, 1.4 mol), ethylene carbonate (135.61 g, 1.54 mol), potassium carbonate (212.84 g, 1.54 mol) and DMF (1.8 L) were mixed, stirred and dissolved, heated to 60 °C and reacted for 1.5 h. After the reaction was completed, the system was cooled to room temperature, triethylamine (467.5 g, 4.62 mol) and 4-dimethylaminopyridine (188.14 g, 1.54 mol) were added, stirred and dissolved, cooled to 0 ± 5 °C, and methanesulfonyl chloride (176.41 g, 1.54 mol) was added dropwise. The reaction was carried out at 0 ± 5 °C for 4 h, and then dimethylamine hydrochloride (313.93 g, 3.85 mol) was added, and the temperature was raised to 35 ± 5 °C and reacted for 6 h. After the reaction was completed, the reaction solution was poured into 1 L of water, 2 L of isopropyl acetate was added, stirred evenly, the pH value was adjusted to 3 with 6% hydrochloric acid, the organic phase was discarded, the pH value of the aqueous phase was adjusted to 9 with saturated potassium carbonate solution, and extracted with isopropyl acetate. The organic phase was retained, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine (Compound 3, light yellow oil, 368.41 g, yield 97.33%).

[0076] Step 2: At room temperature, doxylamine (Compound 3, 360.0 g, 1.332 mol), isopropyl acetate (650 mL) and acetone (650 mL) were mixed, stirred and dissolved, cooled to 0 ± 5 °C, and succinic acid (143.97 g, 1.332 mmol) was added thereto. Crystallization was carried out by stirring at 0 ± 5 °C for 4 h, filtered by suction and dried to obtain doxylamine succinate (508.34 g, yield 98.28%, HPLC purity 99.8%).

Claims

1. A method for preparing doxylamine succinate, characterized in that: The synthetic route is as follows: include: Step 1, using 1-phenyl-1-(pyridin-2-yl)-1-ethanol and ethylene carbonate as raw materials, dissolving 1-phenyl-1-(pyridin-2-yl)-1-ethanol and ethylene carbonate in an organic solvent under the protection of nitrogen or inert gas, causing a substitution reaction under the action of an alkali reagent, adding a sulfonyl chloride compound in the presence of an acid binding agent and a catalyst to react, and finally adding a dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride to carry out a substitution reaction; after the reaction is completed, post-treatment is performed to obtain doxylamine; Step 2: Doxylamine and succinic acid undergo a salt-forming reaction in a reaction solvent to obtain doxylamine succinate.

2. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1, the molar ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to ethylene carbonate is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.

15.

3. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1, the organic solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide.

4. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1, the molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the alkaline reagent is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.15; the alkaline reagent is selected from at least one of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium isopropoxide, potassium isopropoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine.

5. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1, the molar ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the catalyst is 1:1 to 1:1.5, preferably 1:1.05 to 1:1.15; the catalyst is 4-dimethylaminopyridine; The molar ratio of the acid binding agent to 4-dimethylaminopyridine is 3:1-3.5:1; the acid binding agent is triethylamine.

6. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1, the molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the sulfonyl chloride compound is 1:1.0 to 1:1.5, preferably 1:1.05 to 1:1.15; the sulfonyl chloride compound is methanesulfonyl chloride or p-toluenesulfonyl chloride.

7. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1, the temperature of the substitution reaction of 1-phenyl-1-(pyridin-2-yl)-1-ethanol and ethylene carbonate is 30-150°C, and the time of the substitution reaction is 1-4 hours; after adding the sulfonyl chloride compound, the reaction temperature is 0±5°C, and the reaction time is 2-12 hours; after adding dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride, the temperature of the substitution reaction is 20-60°C, and the time of the substitution reaction is 2-24 hours; preferably, the temperature of the substitution reaction of 1-phenyl-1-(pyridin-2-yl)-1-ethanol and ethylene carbonate is 50-60°C, and the time of the substitution reaction is 1-4 hours; after adding the sulfonyl chloride compound, the reaction temperature is 0±5°C, and the reaction time is 2-5 hours; after adding dimethylamine tetrahydrofuran solution or dimethylamine hydrochloride, the temperature of the substitution reaction is 35±5°C, and the time of the substitution reaction is 6-8 hours.

8. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1, the post-treatment is as follows: according to the volume ratio of organic solvent to water of 2:1 to 1.8:1, the volume ratio of organic solvent to extraction solvent of 0.9:1 to 1:1, water and extraction solvent are added to the reaction solution, the pH value is adjusted to 3 to 4 with 6% to 10% hydrochloric acid, the organic phase is discarded, the pH value of the aqueous phase is adjusted to 8 to 9 with saturated sodium carbonate solution or saturated potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine; the extraction solvent is ethyl acetate or isopropyl acetate.

9. The method for preparing doxylamine succinate according to claim 1, wherein: In step 2, the molar ratio of doxylamine to succinic acid is 1:0.9 to 1:1.1, preferably 1:0.95 to 1:1.

05.

10. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step 2, the reaction solvent is selected from one or two of acetone, acetonitrile, ethyl acetate, isopropyl acetate, isopropanol, ethanol, and methanol, preferably a mixed solvent of acetone and a solvent selected from ethyl acetate or acetone in a volume ratio of 4:1 to 1:4, more preferably a mixed solvent of acetone and a solvent selected from ethyl acetate or acetone in a volume ratio of 2:1 to 1:1; The temperature of the salt-forming reaction is -10 to 30°C, preferably -5 to 5°C; the time of the salt-forming reaction is 0.5 to 12 hours, preferably 5 to 6 hours.

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