Preparation method of doxylamine succinate

Abstract

The invention belongs to the field of chemical synthesis of medicines, and discloses a preparation method of doxylamine succinate, which comprises the following steps: step 1, by taking 1-phenyl-1-(pyridine-2-yl) 1-ethanol and a compound 3 as raw materials, carrying out substitution reaction on the 1-phenyl-1-(pyridine-2-yl) 1-ethanol and the compound 3 under the action of an alkali reagent to obtain N, N-dimethyl formamide; the preparation method comprises the following steps: adding N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) ethyoxyl] ethylamine; and 2, carrying out a salt forming reaction on the N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) ethyoxyl] ethylamine and succinic acid, so as to obtain the doxylamine succinate. According to the invention, sulfonic acid 2-(dimethylamino) ethyl ester which has a high boiling point and is efficiently converted is used, so that the yield of the product is greatly improved; in addition, the target crystal form can be stably reproduced and obtained in a low-temperature salt forming and crystallization mode. According to the method, the total yield reaches 93.5% or above, and the purity reaches 99.7% or above.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis, specifically relating to a method for preparing doxylamine succinate. Background Technology

[0002] Doxylamine succinate is an ethanol-based antihistamine with antihistamine, anticholinergic, and significant sedative-hypnotic effects. It is highly active with few 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 Chattens' 25mg doxylamine succinate tablets for use in helping with difficulty falling asleep. It became an OTC (over-the-counter) drug in 1979, and in August 2004, LNK approved it as a generic version. On April 8, 2013, the FDA approved an oral extended-release tablet (brand name Diclegis) of doxylamine succinate and pyridoxine hydrochloride for the treatment of pregnant women experiencing nausea and vomiting who do not respond well to conservative treatment.

[0003] Existing chemical synthesis routes for doxylamine succinate mostly begin with 2-acetylpyridine as the starting material, reacting it with Grignard's reagent (made from iodobenzene or bromobenzene) to generate the important intermediate 2-pyridylphenylmethylmethanol. 2-pyridylphenylmethylmethanol then reacts with 2-dimethylaminochloroethane under the action of an organic base to generate doxylamine (chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]ethylamine), which is finally salted with succinic acid to obtain doxylamine succinate. The main methods for preparing doxylamine succinate are as follows:

[0004] Method 1: Using pyridine and acetophenone as 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 and highly toxic mercury and mercuric chloride as catalysts. This process results in low efficiency and yield, complex post-processing, and is difficult to industrialize. The second step involves 2-chloroethyldimethylamine, a controlled substance that is expensive and difficult to store. Furthermore, the use of metallic sodium as a hydrogen-removing agent generates hydrogen gas during the reaction, making it dangerous and unsuitable for large-scale production. This method yields only 75% of the free base.

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

[0008]

[0009] The first step of this reaction route involves a hazardous Grignard reaction, using flammable and explosive diethyl ether as the solvent. Furthermore, 2-pyridylphenylmethylmethanol requires purification via distillation, resulting in low reaction efficiency and complex post-processing. The melting point of 2-pyridylphenylmethylmethanol is 33–34.5°C, making distillation difficult to guarantee product yield and purity, hindering industrialization, and generating toxic benzene byproducts. The second step involves 2-chloroethyldimethylamine, a controlled substance, which is expensive and difficult to store. Its boiling point is 109–110°C. If toluene (boiling point 110.6°C) is used as the reaction solvent, an azeotropic reaction will occur, causing the 2-chloroethyldimethylamine to evaporate and reduce the doxylamine concentration. The conversion rate of doxylamine is affected by the need for excessive or batch feeding, which increases costs. Using xylene (boiling point 138.4–144.4℃) will also cause 2-chloroethyldimethylamine to volatilize, reducing the conversion rate of doxylamine. Furthermore, using sodium amino acid as a dehydrogenating agent generates ammonia gas during the reaction, making it dangerous and unsuitable for large-scale production. Doxylamine requires column chromatography for purification, a method difficult to industrialize, with a free base yield of only 46%. Salt formation in CN102108059A requires freezing at -20℃ for 24 hours, resulting in high energy consumption and making industrial production difficult. The final product yield is low, with an overall yield of approximately 31%.

[0010] Method 3: This method uses 2-acetylpyridine as the starting material, and the specific route is as follows:

[0011]

[0012] The reaction route is similar to Method 2. The first step involves a dangerous Grignard reaction, using flammable and explosive diethyl ether as the solvent. Post-processing is complex, making industrialization difficult, and it also produces toxic benzene byproducts. The second step involves 2-chloroethyldimethylamine, a controlled substance, which is expensive and difficult to store. Its boiling point is 109–110°C. Using xylene as the reaction solvent would cause 2-chloroethyldimethylamine to volatilize, reducing the conversion rate of doxylamine. Furthermore, using sodium amide as a dehydrogenating agent generates ammonia gas during the reaction, making it dangerous and unsuitable for large-scale production. Doxylamine also requires column chromatography purification, a purification method difficult to industrialize. The crude doxylamine succinate is recrystallized twice with acetone, resulting in a low final product yield.

[0013] Method 4: This method uses 2-acetylpyridine as the starting material, and the specific route is as follows:

[0014]

[0015] The first step of this reaction route is similar to the first step of Method 2, also involving a dangerous Grignard reaction. 2-Pyridylphenylmethylmethanol requires purification by distillation, resulting in low reaction efficiency, complex post-processing, and difficulty in ensuring the yield and purity of 2-pyridylphenylmethylmethanol through distillation, making industrialization difficult and generating toxic benzene byproducts. The second step involves a long reaction time (72 hours) between 2-pyridylphenylmethylmethanol and 2-chloroethyldimethylamine hydrochloride. 2-chloroethyldimethylamine hydrochloride is a controlled substance, expensive, and difficult to store. 2-chloroethyldimethylamine hydrochloride will azeotropically react with the reaction solvent toluene, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine. This requires excessive or batch feeding, increasing costs. The yield of the second step is relatively low, approximately 70-80%.

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

[0017]

[0018] The first step of this reaction route uses n-butyllithium, which is spontaneously combustible in water and extremely flammable. The reaction solvent is a flammable and explosive ether (such as diethyl ether), making it unsuitable for large-scale production. The second step involves 2-chloroethyldimethylamine, a controlled substance that is expensive and difficult to store. If toluene is used, 2-chloroethyldimethylamine will azeotropically react with toluene, causing 2-chloroethyldimethylamine to volatilize and thus reducing the conversion rate of doxylamine. This would require excessive or batch feeding, increasing costs. If xylene is used as the reaction solvent, reflux will cause 2-chloroethyldimethylamine to volatilize, reducing the conversion rate of doxylamine. In addition, sodium amide is used as a dehydrogenating agent, which generates ammonia gas during the reaction. Large-scale application is quite dangerous and not suitable for large-scale production.

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

[0020]

[0021] The first step of this reaction route involves a hazardous Grignard reaction, using flammable and explosive diethyl ether as the solvent. Furthermore, 2-pyridylphenylmethylmethanol requires purification by column chromatography, making post-processing complex and hindering industrialization. The second step involves 2-chloroethyldimethylamine, a controlled substance that is expensive and difficult to store. It also reacts with the reaction solvent toluene in an azeotropic reaction, causing 2-chloroethyldimethylamine to evaporate and reduce the conversion rate of doxylamine. This necessitates excessive or batch feeding, increasing costs. Additionally, the use of sodium hydride as a dehydrogenating agent generates hydrogen gas during the reaction, making its application dangerous and unsuitable for large-scale production. Moreover, doxylamine requires purification by column chromatography, a purification method difficult to industrialize. Finally, the final product yield is low.

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

[0023]

[0024] Although this method has a shorter procedure, 2-chloroethyldimethylamine is a controlled substance and is not easy to store. Using xylene as a reaction solvent and refluxing under nitrogen protection will cause 2-chloroethyldimethylamine to volatilize violently, reducing the conversion rate of doxylamine. This requires a large over-feeding, which increases costs. In addition, using sodium amide as a dehydrogenating agent will generate ammonia during the reaction, which is dangerous for large-scale application and is not suitable for large-scale production.

[0025] In summary, the synthetic route for doxylamine succinate has the following drawbacks:

[0026] 1. In the preparation of 2-pyridylphenylmethylmethanol, Method 1 uses highly toxic mercury and mercuric chloride as catalysts and metallic sodium as a hydrogen removal reagent; Methods 2, 3, 4 and 6 all use self-made Grignard reagents, which are highly dangerous and have complex post-processing, making industrialization difficult. In particular, Methods 2, 3 and 4 also produce toxic benzene byproducts; Method 5 uses n-butyllithium, which is spontaneously combustible in water and is extremely flammable. The solvent is a flammable and explosive ether, which is not suitable for large-scale production.

[0027] 2. In the preparation of doxylamine free base, 2-chloroethyldimethylamine or its hydrochloride is used as a raw material, which is expensive and difficult to store. When toluene is used as a reaction solvent, 2-chloroethyldimethylamine and toluene will azeotropically react, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine. When xylene is used as a reaction solvent, the same will happen, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine. Excess or batch feeding is required, which greatly increases the cost. The preparation of doxylamine free base requires the use of sodium metal, sodium amide, or sodium hydride as dehydrogenating agents. These are superbases that react violently and rapidly with water, which can easily cause dangers such as spraying and explosion. They are not suitable for large-scale production. Moreover, the reaction time is long, and the free base doxylamine needs to be separated and purified by column chromatography, which makes industrialization difficult.

[0028] 3. Although Method 7 has made significant technical improvements by directly using 2-pyridylphenylmethylmethanol as a raw material in a two-step reaction to prepare the product, the preparation of doxylamine free base still inevitably involves the excessive use of 2-chloroethyldimethylamine and sodium amide, which is explosive, dangerous to operate, and difficult to industrialize. In particular, the reaction to adjust the base is a xylene reflux reaction, and the boiling point of xylene is much higher than that of 2-chloroethyldimethylamine, resulting in increased costs and reduced conversion rate.

[0029] It is evident that current chemical synthesis techniques for doxylamine succinate suffer from numerous shortcomings, including low yield, cumbersome post-processing, high cost, high toxicity, safety hazards, and inability to support large-scale industrial production. Therefore, developing new synthetic processes to improve yield, simplify procedures, reduce costs, and create a suitable industrial-scale production process for doxylamine succinate is of great significance. Summary of the Invention

[0030] The purpose of this invention is to provide a method for preparing doxylamine succinate.

[0031] The objective of this invention is achieved through the following technical solution:

[0032] A method for preparing doxylamine succinate, the synthetic route is as follows:

[0033]

[0034] Wherein, R1 is selected from Tos (p-toluenesulfonic acid group) or Ms (methanesulfonic acid group); R2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, and H;

[0035] Includes the following steps:

[0036] Step 1: Using 1-phenyl-1-(pyridin-2-yl)1-ethanol (compound 2) and compound 3 as raw materials, under the action of a base reagent, 1-phenyl-1-(pyridin-2-yl)1-ethanol and compound 3 undergo a substitution reaction to obtain N,N-dimethyl-2-[1-phenyl-1-(2-pyridin)ethoxy]ethylamine (i.e., doxylamine, compound 4);

[0037] Step 2: N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine reacts with succinic acid to form a salt, yielding doxylamine succinate (N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine succinate, compound 1).

[0038] In step one, the chemical name of intermediate 3 is: 2-(dimethylamino)ethyl p-toluenesulfonic acid (CAS No: 123091-15-6) or 2-(dimethylamino)ethyl methanesulfonic acid (CAS No: 44929-30-8).

[0039] The molar ratio of 1-phenyl-1-(pyridin-2-yl)1-ethanol to compound 3 is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.2.

[0040] The molar ratio of 1-phenyl-1-(pyridin-2-yl)1-ethanol to the base reagent is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.2.

[0041] The alkaline reagent is a metal alkaline reagent, specifically selected from one or more of the following: sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, potassium isopropoxide, sodium hydroxide, and potassium hydroxide.

[0042] The reaction solvent is selected from one or two of toluene, xylene, tetrahydrofuran, acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMAC).

[0043] The mass-to-volume ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the reaction solvent is 1:1 to 1:20 g / mL, preferably 1:3 to 1:10 g / mL, and more preferably 1:5 to 1:8 g / mL.

[0044] The temperature of the substitution reaction is 40°C to the reflux temperature corresponding to the reaction solvent, preferably 60°C to 100°C; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours.

[0045] After the substitution reaction is complete, water is added to the reaction solution at a volume ratio of 1:0.5 to 1:2.5 between the reaction solvent and water. 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 or 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 and concentrated to obtain N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine.

[0046] Preferably, in some cases, when the reaction solvent is tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N,N-dimethylacetamide, after the substitution reaction is completed, water is added to the reaction solution at a volume ratio of reaction solvent to water of 0.75:1 to 1:2.5, and ethyl acetate or isopropyl acetate is added as the extraction solvent at a volume ratio of reaction solvent to extraction solvent of 0.6:1 to 1:1. 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 or potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, the organic phase is dried with anhydrous sodium sulfate, concentrated, and N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine is obtained.

[0047] Preferably, in some cases, when the reaction solvent is toluene or xylene, after the substitution reaction is completed, water is added to the reaction solution at a volume ratio of 1:0.5 to 1:0.8 of the reaction solvent to water, 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 or potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, the organic phase is dried with anhydrous sodium sulfate and concentrated to obtain N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine.

[0048] In step two, the molar ratio of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine to succinic acid is 1:0.9 to 1:1.1, preferably 1:0.95 to 1:1.05, and more preferably 1:1.

[0049] The reaction solvent is selected from one or two of acetone, ethyl acetate, and isopropyl acetate, preferably a mixture of acetone and ethyl acetate in a volume ratio of 4:1 to 1:4. Specifically, the reaction solvent can be a mixture of acetone and ethyl acetate in a volume ratio of 3:1, or a mixture of acetone and isopropyl acetate in a volume ratio of 1:1.

[0050] The mass-to-volume ratio of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine to the reaction solvent is 1:1 to 1:10 g / mL, preferably 1:2 to 1:6 g / mL.

[0051] 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.

[0052] Preferably, after crystallization, the sample is filtered and dried to obtain doxylamine succinate.

[0053] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0054] This invention provides a novel method for preparing doxylamine succinate, which is of great significance for the research and process control of doxylamine succinate.

[0055] This invention avoids the excessive use of expensive, low-boiling-point tubular material 2-chloroethyldimethylamine or its hydrochloride as raw material, and uses 2-(dimethylamino)ethyl sulfonic acid, which has a higher boiling point and high conversion efficiency, to greatly improve the product yield. In addition, the low-temperature salt formation and crystallization method can stably reproduce the target crystal form.

[0056] The present invention features a short reaction route, mild reaction conditions, and simple operation. Throughout the reaction process, it is highly safe, low in cost, has good stability, and is easy to process. The overall yield reaches over 94%, and the purity reaches over 99.8%. Attached Figure Description

[0057] Figure 1 The 1H NMR spectrum of doxylamine succinate prepared in Example 1 is shown.

[0058] Figure 2 The image shows the differential thermal analysis (DSC) spectrum of doxylamine succinate prepared in Example 1.

[0059] Figure 3 The liquid phase purity spectrum of doxylamine succinate prepared in Example 1 is shown.

[0060] Figure 4 The differential thermal analysis (DSC) spectrum of doxylamine succinate prepared in Comparative Example 1 is shown. Detailed Implementation

[0061] The following embodiments further illustrate the technical solution of the present invention. These embodiments are only used to illustrate preferred embodiments of the present invention in a more specific way and are not intended to limit the technical solution of the present invention. Any methods and materials similar to or equivalent to the contents herein may be used in the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as known to those skilled in the art.

[0062] Experimental methods in the following examples, unless otherwise specified, are generally prepared under conventional conditions.

[0063] Example 1

[0064] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)1-ethanol (compound 2, 199.25 g, 1.0 mol), 2-(dimethylamino)ethyl p-toluenesulfonic acid (267.65 g, 1.1 mol), sodium tert-butoxide (105.71 g, 1.1 mol), and xylene (1.2 L) were mixed, stirred to dissolve, and heated to 100 °C for 3 h. After the reaction was completed, 600 mL of water was added, and the mixture was stirred for 0.5 h. The pH was adjusted to 4 with 6% hydrochloric acid, the organic phase was discarded, and the pH of the aqueous phase was adjusted to 9 with saturated sodium carbonate solution. Ethyl acetate was added for extraction, and the organic phase was retained. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4 (N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]ethylamine, a pale yellow oil, 268.32 g, yield 99.24%).

[0065] Step 2: At room temperature, compound 4 (250.0 g, 0.925 mmol), ethyl acetate (250 mL), and acetone (750 mL) were stirred and dissolved. The mixture was cooled to 0 ± 5 °C, and succinic acid (109.19 g, 0.925 mmol) was added. The mixture was stirred at 0 ± 5 °C for 5 h to crystallize. The crystals were then filtered and dried to obtain doxylamine succinate (342.26 g, yield 95.25%, HPLC purity 99.9%).

[0066] 1 H NMR (400MHz, DMSO-d6) δ: 8.48 (m, 1H, NH), 7.62 (s, 2H, Ar-H), 7.76 (m, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.29 (s, 2H, Ar-H), 7.22 (m, 2H, Ar-H ), 7.17 (m, 2H, Ar-H), 6.30 (s, 2H, COOH), 3.42 (m, 2H, -CH2), 2.81 (m, 2H, -CH2), 2.38 (s, 6H, -CH3), 2.38 (s, 4H, -CH2), 1.93 (s, 3H, -CH3).

[0067] The DSC chromatogram of doxylamine succinate is shown below. Figure 2 There is a sharp endothermic peak at around 104.64℃ to 106.60℃.

[0068] Comparative Example 1

[0069] Repeat Example 1 of CN105237467A, as follows:

[0070] S1: Dissolve 200g of 2-pyridylphenylmethylmethanol in 1L of xylene. Under nitrogen protection, cool the system to 0-5℃, add 222g of sodium amino, stir for 30 minutes, add 1.07kg of dimethylaminochloroethane hydrochloride, continue to keep warm at 0-5℃ and stir for 20 minutes, slowly raise the temperature to 140℃, and reflux and stir for 1 hour. After the reaction is complete, cool to 0-5℃, add 500mL of 25% ammonium chloride dropwise, stir for 30 minutes, let stand and separate the layers, discard the aqueous layer, add 300mL of 4% dilute hydrochloric acid, mix thoroughly for 15 minutes, let stand and separate the layers, discard the organic phase, add 300mL of 25% sodium carbonate aqueous solution and 1L of ethyl acetate to the aqueous phase, mix thoroughly, let stand and separate the layers, dry the ethyl acetate layer with anhydrous sodium sulfate, filter, and remove ethyl acetate by vacuum distillation to obtain doxylamine (pale yellow oil, 214.50g, yield 79.03%). Experiments show that the product yield is lower than that of Example 1 in CN105237467A due to the vigorous volatilization of dimethylaminochloroethane.

[0071] S2: Dissolve 136g of doxylamine in a 1.36L mixture of isopropanol and ethyl acetate (1:1, V / V). Add 59.5g of succinic acid at 25℃, heat to 60℃, stir for 1h, slowly cool to 0-5℃, and stir to crystallize for 5h. After the reaction, filter under nitrogen protection. Wash the filter cake with 100mL of isopropanol and 200mL of ethyl acetate, respectively. Dry the filter cake under reduced pressure at 45℃ and p>0.08MPa for 8h to obtain doxylamine succinate (white solid, 157.26g, yield 80.49%, HPLC purity 99.7%). Experiments show that the yield of the product obtained by this method is lower than that of Example 1 in CN105237467A, and DSC shows a sharp endothermic peak around 94.74℃~97.77℃, indicating that the product is a different crystal form, likely due to crystallization after thermal dissolution.

[0072] Example 2

[0073] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 199.25 g, 1.0 mol), 2-(dimethylamino)ethyl p-toluenesulfonic acid (267.65 g, 1.1 mol), potassium tert-butoxide (123.43 g, 1.1 mol), and toluene (1.4 L) were mixed, stirred to dissolve, and heated to 80 °C for 4 h. After the reaction was complete, 1 L of water was added, and the mixture was stirred for 0.5 h. The pH was adjusted to 3 with 8% hydrochloric acid, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 9 with saturated sodium carbonate solution, and ethyl acetate was added for extraction. The organic phase was retained, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4 (pale yellow oil, 266.81 g, yield 98.68%).

[0074] Step 2: Compound 4 (260.0 g, 0.962 mmol), ethyl acetate (260 mL), and acetone (780 mL) were dissolved by stirring at room temperature. The mixture was then cooled to 0 ± 5 °C, and succinic acid (113.60 g, 0.962 mmol) was added. The reaction mixture was stirred at 0 ± 5 °C for 6 h to crystallize. The solution was then filtered and dried to obtain doxylamine succinate (356.66 g, yield 95.44%, HPLC purity 99.8%).

[0075] Example 3

[0076] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 199.25 g, 1.0 mol), 2-(dimethylamino)ethyl methanesulfonate (183.95 g, 1.1 mol), sodium tert-butoxide (105.71 g, 1.1 mol), and DMF (600 mL) were mixed, stirred to dissolve, and heated to 70 °C for 3 h. After the reaction was complete, 800 mL of water was added, and the mixture was stirred for 0.5 h. Then, 1 L of isopropyl acetate was added, and the pH was adjusted to 4 with 6% hydrochloric acid. The organic phase was discarded, and the pH of the aqueous phase was adjusted to 9 with saturated potassium carbonate solution. Isopropyl acetate was added for extraction, and the organic phase was retained. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4 (pale yellow oil, 267.59 g, yield 98.97%).

[0077] Step 2: At room temperature, compound 4 (260.0 g, 0.962 mmol), isopropyl acetate (520 mL), and acetone (520 mL) were stirred and dissolved. The mixture was cooled to 0 ± 5 °C, and succinic acid (113.60 g, 0.962 mmol) was added. The reaction mixture was stirred at 0 ± 5 °C for 6 h to crystallize. The solution was then filtered and dried to obtain doxylamine succinate (358.23 g, yield 95.86%, HPLC purity 99.8%).

Claims

1. A method for preparing doxylamine succinate, characterized in that: The synthesis route is as follows: Wherein, R1 is selected from p-toluenesulfonic acid group or methanesulfonic acid group; R2 is selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, H; Includes the following steps: Step 1: Using 1-phenyl-1-(pyridin-2-yl)1-ethanol and compound 3 as raw materials, under the action of a base reagent, 1-phenyl-1-(pyridin-2-yl)1-ethanol and compound 3 undergo a substitution reaction to give N,N-dimethyl-2-[1-phenyl-1-(2-pyridin)ethoxy]ethylamine; Step 2: N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine reacts with succinic acid to form a salt, yielding doxylamine succinate.

2. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step one, the molar ratio of 1-phenyl-1-(pyridin-2-yl)1-ethanol to compound 3 is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.

2.

3. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step one, the molar ratio of 1-phenyl-1-(pyridin-2-yl)1-ethanol to the alkaline reagent is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.

2.

4. The method for preparing doxylamine succinate according to claim 1 or 3, characterized in that: In step one, the alkaline reagent is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, potassium isopropoxide, sodium hydroxide, and potassium hydroxide.

5. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step one, the reaction solvent is selected from one or two of toluene, xylene, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N,N-dimethylacetamide.

6. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step one, the temperature of the substitution reaction is 40°C to the reflux temperature corresponding to the reaction solvent, preferably 60°C to 100°C; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours.

7. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step one, after the substitution reaction is complete, water is added to the reaction solution at a volume ratio of 1:0.5 to 1:2.5 (reaction solvent to water). The pH is adjusted to 3 to 4 with 6% to 10% hydrochloric acid. The organic phase is discarded. The pH of the aqueous phase is adjusted to 8 to 9 with saturated sodium carbonate or potassium carbonate solution. Ethyl acetate or isopropyl acetate is added for extraction, and the organic phase is retained. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine. Preferably, when the reaction solvent is tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N,N-dimethylacetamide, after the substitution reaction is complete, water is added to the reaction solution at a volume ratio of 0.75:1 to 1:2.5 (reaction solvent to water). Ethyl acetate or isopropyl acetate is added as the extraction solvent at a volume ratio of 0.6:1 to 1:1 (reaction solvent to extraction solvent). The reaction solvent is toluene or xylene. After the substitution reaction is complete, water is added to the reaction solution at a volume ratio of 1:0.5 to 1:0.

8. The pH of the aqueous phase is adjusted to 3-4 with 6%-10% hydrochloric acid, the organic phase is discarded, and the pH of the aqueous phase is adjusted to 8-9 with saturated sodium carbonate or potassium carbonate solution. The aqueous phase is then extracted with ethyl acetate or isopropyl acetate, and the organic phase is retained. The organic phase is dried with anhydrous sodium sulfate and concentrated to obtain N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine.

8. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step two, the molar ratio of N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine to succinic acid is 1:0.9 to 1:1.1, preferably 1:0.95 to 1:1.05, and more preferably 1:

1.

9. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step two, the reaction solvent is selected from one or two of acetone, ethyl acetate, and isopropyl acetate, preferably a mixed solvent of acetone and one of ethyl acetate and isopropyl acetate in a volume ratio of 4:1 to 1:

4.

10. The method for preparing doxylamine succinate according to claim 1, characterized in that: In step two, the temperature of the salt formation reaction is -10 to 30°C, preferably -5 to 5°C; the time of the salt formation reaction is 0.5 to 12 hours, preferably 5 to 6 hours.

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