Preparation method of doxylamine succinate

Abstract

The invention discloses a doxylamine succinate preparation method, which comprises: carrying out a substitution reaction on 1-phenyl-1-(pyridine-2-yl) 1-ethanol and a substituted ethane derivative represented by a formula # imgabs0 #, and adding a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride to carry out a reaction in the presence of an acid-binding agent, and carrying out post-treatment to obtain doxylamine. Or 1-phenyl-1-(pyridine-2-yl) 1-ethanol and an N-(t-butyloxycarboryl)-2-ethylamine derivative shown as a formula # imgabs 1 # are subjected to a substitution reaction, then a deprotection reaction is carried out under the acidic condition to remove a Boc protecting group, and a methylation reagent is added for a methylation reaction; and carrying out post-treatment to obtain doxylamine. The doxylamine and succinic acid are subjected to a salt forming reaction to obtain the doxylamine succinate. The method is short in reaction route, mild in reaction condition, simple and convenient to operate and simple in post-treatment; the total yield reaches about 90% or above, and the purity reaches 99.8% or above.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing doxylamine succinate. Background Art

[0002] Doxylamine succinate is an ethanol antihistamine with antihistamine, anticholinergic and significant sedative and hypnotic effects. It is highly active and has low gastrointestinal side effects. It is suitable for a variety of allergic skin diseases, hay fever, allergic rhinitis, asthmatic bronchitis and short-term treatment of insomnia. In October 1978, the FDA approved the marketing of doxylamine succinate 25mg tablets from CHATTEM to help with difficulty falling asleep. It became an OTC (over-the-counter drug) in 1979 and was officially approved by LNK as a generic drug in August 2004. 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 women with nausea and vomiting during pregnancy 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, which reacts with a Grignard reagent made of iodobenzene or bromobenzene to generate an important intermediate 2-pyridylphenylmethylmethanol, which then reacts with 2-dimethylaminoethyl chloride in the presence 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:

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

[0005]

[0006] The first step of the reaction route is a condensation reaction, using metal aluminum or magnesium gold and toxic mercury and mercuric chloride as catalysts, with low reaction efficiency and yield, complicated post-processing, and difficult to industrialize; the second step 2-chloroethyldimethylamine is a controlled product, expensive, and difficult to store. In addition, metal sodium is used as a hydrogen extraction reagent, and hydrogen will be generated during the reaction, which is more dangerous and not suitable for large-scale production operations. The yield of the free base prepared by this method is only 75%.

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

[0008]

[0009] The first step of the reaction route involves a dangerous Grignard reaction, the solvent is flammable and explosive ether, and 2-pyridylphenylmethylmethanol needs to be purified by distillation, the reaction efficiency is low, the post-processing is complicated, the melting point of 2-pyridylphenylmethylmethanol is 33-34.5°C, distillation is difficult to ensure product yield and purity, industrialization is difficult, and toxic benzene by-products will be produced; the second step 2-chloroethyldimethylamine is a controlled product, expensive, and difficult to store, its boiling point is 109-110°C, if toluene (boiling point is 110.6°C) is used as the reaction solvent, the two will produce azeotropy, which will cause 2-chloroethyldimethylamine to volatilize and reduce doxylamine The conversion rate of doxylamine needs to be increased by excessive or batch feeding, which increases the cost. If xylene (boiling point is 138.4-144.4°C) is used, 2-chloroethyldimethylamine will also be volatilized to reduce the conversion rate of doxylamine; in addition, sodium amide is used as a hydrogen extraction reagent, and ammonia will be generated during the reaction, which is dangerous to use and not suitable for large-scale production operations; and doxylamine needs to be separated and purified by column chromatography, which is difficult to industrialize, and the yield of the free base is only 46%; the salt in CN102108059A needs to be frozen at -20°C for 24 hours, which consumes a lot of energy and is not easy 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 dangerous Grignard reaction, and the solvent is flammable and explosive ether. The post-processing is complicated and difficult to industrialize. In addition, toxic benzene by-products will be produced. In the second step, 2-chloroethyldimethylamine is a controlled product, expensive, and difficult to store. Its boiling point is 109-110°C. If xylene is used as a reaction solvent, 2-chloroethyldimethylamine will evaporate and reduce the conversion rate of doxylamine. In addition, sodium amide is used as a hydrogen extraction reagent, and ammonia will be produced during the reaction. It is more dangerous to use and not suitable for large-scale production operations. Doxylamine needs to be separated and purified by column chromatography, and this purification method is difficult to industrialize. The crude doxylamine succinate 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, and also involves a dangerous Grignard reaction. 2-pyridylphenylmethylmethanol needs to be purified by distillation, which has low reaction efficiency and complicated post-processing. It is difficult to ensure the yield and purity of 2-pyridylphenylmethylmethanol by distillation, which is difficult to industrialize and will produce toxic benzene by-products. In the second step, the reaction time of 2-pyridylphenylmethylmethanol and 2-chloroethyldimethylamine hydrochloric acid is relatively long (72h). 2-chloroethyldimethylamine hydrochloric acid is a controlled product, expensive, and difficult to store. 2-chloroethyldimethylamine hydrochloric acid will azeotrope with the reaction solvent toluene, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine, requiring excessive or batch feeding, which increases the cost. The yield of the second step is low, about 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 the reaction route uses n-butyl lithium, which is self-igniting when it comes into contact with water and is extremely flammable. The reaction solvent is flammable and explosive ethers (such as diethyl ether), which is not suitable for large-scale production operations. The second step 2-chloroethyldimethylamine is a controlled product, expensive, and difficult to store. If toluene is used, 2-chloroethyldimethylamine will azeotrope with toluene, causing 2-chloroethyldimethylamine to volatilize and thus reduce the conversion rate of doxylamine, requiring excessive or batch feeding, which increases costs. If xylene is used as the reaction solvent, 2-chloroethyldimethylamine will volatilize during the reflux reaction, thereby reducing the conversion rate of doxylamine. In addition, sodium amide is used as a hydrogen extraction reagent, and ammonia gas will be generated during the reaction. It is dangerous to use it in large quantities and is not suitable for large-scale production operations.

[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, and the solvent is flammable and explosive ether, and 2-pyridylphenylmethylmethanol needs to be purified by column chromatography, which makes post-processing complicated and difficult to industrialize. In the second step, 2-chloroethyldimethylamine is a controlled product, expensive, and difficult to store. It will azeotropy with the reaction solvent toluene, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine. It needs to be added in excess or in batches, which increases the cost. In addition, sodium hydride is used as a hydrogen extraction reagent, and hydrogen will be generated during the reaction. It is relatively dangerous to use and not suitable for large-scale production operations. 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 low.

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

[0023]

[0024] Although the method has a short number of steps, 2-chloroethyldimethylamine is a controlled product and is not easy to store. Using xylene as a reaction solvent for reflux reaction under nitrogen protection will cause 2-chloroethyldimethylamine to evaporate violently, thereby reducing the conversion rate of doxylamine and requiring a large amount of excess feed, which increases the cost. In addition, using sodium amide as a hydrogen extraction reagent will produce ammonia during the reaction, which is dangerous for large-scale use and is not suitable for large-scale production operations.

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

[0026] 1. When preparing 2-pyridylphenylmethylcarbinol, method 1 uses highly toxic mercury and mercuric chloride as catalysts and metallic sodium as a hydrogen extraction reagent; methods 2, 3, 4 and 6 all use homemade Grignard reagents, which are highly dangerous, and have complex post-processing and are difficult to industrialize. In particular, methods 2, 3 and 4 will also produce toxic benzene by-products; method 5 uses n-butyl lithium, which is self-igniting when exposed to water and is very flammable. The solvent is flammable and explosive ethers, which is not suitable for large-scale production operations;

[0027] 2. When preparing doxylamine free base, controlled 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 produce an azeotropic reaction, causing 2-chloroethyldimethylamine to volatilize and reduce the conversion rate of doxylamine. When xylene is used as a reaction solvent, 2-chloroethyldimethylamine will also reduce the conversion rate of doxylamine due to volatilization, and excessive or batch feeding is required, which greatly increases the cost. When preparing doxylamine free base, sodium metal, sodium amide or sodium hydride hydrogen extraction reagents are required. They are super bases, and they react violently and quickly with water, which is prone to spraying, explosion and other dangers. They are not suitable for large-scale production operations, and the reaction time is long. Free base doxylamine needs to be separated and purified by column chromatography, which makes industrialization difficult.

[0028] 3. Although method 7 has made great technical improvements and directly uses 2-pyridylphenylmethylmethanol as a raw material to prepare the product in a two-step reaction, the preparation of doxylamine free base still cannot avoid the excessive use of 2-chloroethyldimethylamine and sodium amide, which is explosive, dangerous to operate, and difficult to industrialize; in particular, the alkali adjustment reaction 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 rates.

[0029] It can be seen that the current chemical synthesis technology of doxylamine succinate has many shortcomings such as low yield, cumbersome post-processing, high cost, high toxicity, potential safety hazards, and inability to industrialize large-scale production. Therefore, it is of great significance to develop a new synthesis process to improve the yield, simplify the operation steps, and reduce the cost, so as to make a doxylamine succinate process suitable for industrialized large-scale production. Summary of the invention

[0030] The object of the present invention is to provide a method for preparing doxylamine succinate.

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

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

[0033]

[0034] Among them, R 1 , R 2 are independently selected from fluorine, chlorine, bromine, iodine, sulfonate R 3 Selected from methyl, p-methylphenyl; preferably, R 1 , R 2 are independently selected from bromine, iodine, and sulfonate groups; more preferably, R 1 =R 2 = sulfonate group;

[0035] or

[0036]

[0037] Wherein, R is selected from fluorine, chlorine, bromine, iodine, sulfonate R 3 is selected from methyl and p-methylphenyl; preferably, R is selected from bromine, iodine and sulfonate; more preferably, R is selected from sulfonate;

[0038] The following steps are involved:

[0039] Step 1, method 1: 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2) and formula The substituted ethane derivative (compound 3a) shown is used as a raw material, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and the substituted ethane derivative are dissolved in an organic solvent under the protection of nitrogen or inert gas, and 1-phenyl-1-(pyridin-2-yl)-1-ethanol and the substituted ethane derivative undergo a substitution reaction under the action of an alkaline reagent, and then a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride is added in the presence of an acid binding agent to react; after the reaction is completed, doxylamine (compound 4) is obtained by post-treatment;

[0040] Or method 2: 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2) and formula The N-(tert-butoxycarbonyl)-2-ethylamine derivative (compound 3b) shown is used as a raw material. Under the protection of nitrogen or inert gas, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and N-(tert-butoxycarbonyl)-2-ethylamine derivatives are dissolved in an organic solvent. Under the action of an alkaline reagent, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and N-(tert-butoxycarbonyl)-2-ethylamine derivatives undergo a substitution reaction, and then a deprotection reaction is carried out under acidic conditions to remove the Boc protecting group, and a methylating agent is added to carry out a methylation reaction; after the reaction is completed, doxylamine (compound 4) is obtained by post-treatment; wherein the methylating agent is paraformaldehyde and formic acid;

[0041] Step 2: Doxylamine (Compound 4) reacts with succinic acid in an organic solvent to form a salt to obtain doxylamine succinate (Compound 1, chemical name: N,N-dimethyl-2-[1-phenyl-1-(2-pyridine)ethoxy]ethylamine succinate).

[0042] In step 1 of method 1, the molar ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the substituted ethane derivative is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.2, and more preferably 1:1.05 to 1:1.1.

[0043] Preferably, R 1 , R 2 are independently selected from bromine, iodine, sulfonate R 3 Selected from methyl and p-methylphenyl.

[0044] More preferably, R 1 =R 2 =Sulfonate R 3 Selected from methyl and p-methylphenyl.

[0045] Specifically, the substituted ethane derivative may be 1,2-bis(p-toluenesulfonyloxy)ethane (CAS No: 6315-52-2) or 1,2-bis(methanesulfonyloxy)ethane (CAS No: 4672-49-5).

[0046] The molar ratio of the 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, and more preferably 1:1.05 to 1:1.1.

[0047] 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, cesium carbonate, sodium bicarbonate, triethylamine, N,N-diisopropylethylamine, etc.

[0048] The organic solvent is selected from one or more of toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like, preferably tetrahydrofuran, acetonitrile, N,N-dimethylformamide (DMF).

[0049] The mass volume ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the organic 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.

[0050] The temperature of the substitution reaction is 20° C. to the reflux temperature of the organic solvent, preferably 30 to 90° C.; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours.

[0051] Preferably, after the substitution reaction is completed, the mixture is cooled to room temperature, a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride and an acid binding agent are added, and the temperature is raised to 20 to 80° C. for reaction for 1 to 12 hours.

[0052] More preferably, after the substitution reaction is completed, the mixture is cooled to room temperature, a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride and an acid binding agent are added, and the temperature is raised to 30 to 60° C. to react for 5 to 8 hours.

[0053] The molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to dimethylamine or its hydrochloride is 1:1.0 to 1:8.0, preferably 1:2.0 to 1:4.0, and specifically 1:2.1. The molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the acid binding agent is 1:1.0 to 1:8.0, preferably 1:2.0 to 1:4.0, and specifically 1:2.1.

[0054] The acid binding agent is an organic base; the organic base is selected from at least one of triethylamine and N,N-diisopropylethylamine.

[0055] The post-treatment comprises the following steps: after the reaction is completed, water is added to the reaction solution according to a volume ratio of an organic solvent to water of 0.75:1 to 1.25:1, a pH value is adjusted to 3 to 4 with 6% to 10% hydrochloric acid, an organic phase is discarded, a saturated sodium carbonate solution or a saturated potassium carbonate solution is used to adjust the pH value of the aqueous phase to 8 to 9, ethyl acetate or isopropyl acetate is added for extraction, an organic phase is retained, the organic phase is dried over anhydrous sodium sulfate, and concentrated to obtain doxylamine.

[0056] Preferably, when the reaction solvent is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide, after the reaction is completed, water is added to the reaction solution at a volume ratio of 0.75:1 to 1.25:1 for the organic solvent and water, ethyl acetate or isopropyl acetate is added as an extraction solvent at a volume ratio of 0.6:1 to 1:1 for the organic solvent and extraction solvent, 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 a saturated sodium carbonate solution or a saturated potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain doxylamine.

[0057] In step 1 of method 2, the molar ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to N-(tert-butyloxycarbonyl)-2-ethylamine derivative is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.2, and more preferably 1:1.05 to 1:1.1.

[0058] Preferably, R is selected from bromine, iodine, sulfonate R 3 Selected from methyl and p-methylphenyl.

[0059] More preferably, R is selected from sulfonate groups R 3 Selected from methyl and p-methylphenyl.

[0060] Specifically, the N-(tert-butoxycarbonyl)-2-ethylamine derivative can be 2-([tert-butoxycarbonyl]amino)ethyl p-toluenesulfonate (CAS No: 158690-56-3) or 2-([tert-butoxycarbonyl]amino)ethyl methanesulfonate (CAS No: 96628-67-0).

[0061] The molar ratio of the 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, and more preferably 1:1.05 to 1:1.1.

[0062] 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, cesium carbonate, sodium bicarbonate, triethylamine, N,N-diisopropylethylamine, etc.

[0063] The organic solvent is selected from one or more of methyltetrahydrofuran, acetonitrile, toluene, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMAC), and dioxane, preferably one or two of toluene, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

[0064] The mass volume ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the organic 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.

[0065] The temperature of the substitution reaction is 40° C. to 150° C., preferably 60° C. to 110° C.; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours.

[0066] Preferably, after the substitution reaction is completed, the mixture is cooled to room temperature, an acid is added, and the mixture is heated under acidic conditions to perform a deprotection reaction to remove the Boc protecting group; after the reaction is completed, paraformaldehyde and formic acid are added to the reaction system to perform a methylation reaction.

[0067] The acid is selected from concentrated hydrochloric acid, formic acid or trifluoroacetic acid; the temperature of the deprotection reaction is 20 to 80° C., preferably 30 to 60° C.; the time of the deprotection reaction is 1 to 12 hours, preferably 2 to 5 hours.

[0068] The temperature of the methylation reaction is 50 to 150° C., preferably 80 to 115° C.; the time of the methylation reaction is 1 to 12 hours, preferably 6 to 10 hours.

[0069] The molar ratio of the paraformaldehyde (the amount of substance of the paraformaldehyde is calculated by dividing the mass of the paraformaldehyde by the relative molecular weight 30 of a repeating unit) to 1-phenyl-1-(pyridin-2-yl)-1-ethanol is 2:1 to 16:1, preferably 3:1 to 5:1, and specifically 4:1.

[0070] The molar ratio of formic acid to 1-phenyl-1-(pyridin-2-yl)-1-ethanol is 3:1 to 32:1, preferably 4.5:1 to 10:1, and more preferably 6.5:1 to 8:1.

[0071] After the methylation reaction is completed, the post-treatment is as follows: adding water to the reaction solution according to a volume ratio of organic solvent to water of 0.75:1 to 1.25:1, adjusting the pH value to 3 to 4 with 6% to 10% hydrochloric acid, discarding the organic phase, adjusting the pH value of the aqueous phase to 8 to 9 with a saturated sodium carbonate or potassium carbonate solution, adding ethyl acetate or isopropyl acetate for extraction, retaining the organic phase, and drying the organic phase over anhydrous sodium sulfate and concentrating to obtain doxylamine.

[0072] Preferably, when the reaction solvent is N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide, after the methylation reaction is completed, water is added to the reaction solution according to a volume ratio of the reaction solvent to water of 0.75:1 to 1.25:1, ethyl acetate or isopropyl acetate is added as an extraction solvent according to a volume ratio of the reaction solvent to the 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 a saturated sodium carbonate or potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain doxylamine.

[0073] 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, and more preferably 1:1.

[0074] The reaction solvent is selected from one or more of acetone, acetonitrile, ethyl acetate, isopropyl acetate, isopropanol, ethanol, and methanol, preferably a mixed solvent of acetone and one selected from ethyl acetate and isopropyl acetate in a volume ratio of 4:1 to 1:4. Specifically, the reaction solvent can be selected from a mixed solvent of acetone and ethyl acetate in a volume ratio of 0.75:1 to 1:1, or a mixed solvent of acetone and isopropyl acetate in a volume ratio of 0.75:1 to 1.5:1.

[0075] The mass volume ratio of doxylamine to the reaction solvent is 1:1 to 1:10 g / mL, preferably 1:2 to 1:8 g / mL, and more preferably 1:5 to 1:6 g / mL.

[0076] 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 4 to 6 hours.

[0077] Preferably, the salt-forming reaction is accompanied by crystallization, and after the crystallization is completed, the mixture is filtered and dried to obtain doxylamine succinate.

[0078] Compared with the prior art, the present invention has the following beneficial effects:

[0079] (1) The present invention utilizes 1-phenyl-1-(pyridin-2-yl)-1-ethanol to react with a sulfonate side chain with a higher boiling point, and then introduces a methyl group (method 1 is a substitution reaction, and method 2 uses an Eschweiler-Clark reaction), prepares doxylamine by a one-pot method, and then forms a salt to obtain a doxylamine succinate product, thereby avoiding cumbersome operations, facilitating the process control of doxylamine succinate, and having important significance for the process research and process control of doxylamine succinate. In addition, the low-temperature salt formation and crystallization method can stably reproduce the target crystal form.

[0080] (2) The raw materials of the present invention are easily available, thus avoiding the use of the expensive controlled reagent 2-chloroethyldimethylamine. The reagents used are all conventional reagents with low cost.

[0081] (3) The present invention has a short reaction route for preparing doxylamine succinate, mild reaction conditions, and simple operation. In the entire reaction process, the invention has high safety, low cost, good stability, and simple post-processing, and is suitable for industrial large-scale production.

[0082] (4) The total yield of doxylamine succinate obtained by the method of the present invention reaches about 90% or more, and the purity reaches 99.8% or more. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 This is the hydrogen spectrum of doxylamine succinate prepared in Example 1.

[0084] Figure 2 This is the liquid phase purity spectrum of doxylamine succinate prepared in Example 1.

[0085] Figure 3 This is the differential thermal analysis (DSC) of doxylamine succinate prepared in Example 1.

[0086] Figure 4 This is the hydrogen spectrum of doxylamine succinate prepared in Example 4.

[0087] Figure 5 This is the liquid phase purity spectrum of doxylamine succinate prepared in Example 4.

[0088] Figure 6 This is the differential thermal analysis (DSC) of doxylamine succinate prepared in Example 4. DETAILED DESCRIPTION

[0089] The technical scheme of the present invention is further illustrated by the following examples, which are only used to more specifically illustrate the preferred embodiments of the present invention and are not used to limit the technical scheme of the present invention. Any method and material similar or equivalent to the contents contained herein 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.

[0090] The experimental methods in the following examples without specifying specific conditions were generally prepared according to conventional conditions.

[0091] Example 1

[0092] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 1,2-bis(p-toluenesulfonyloxy)ethane (777.92 g, 2.1 mol), potassium tert-butoxide (235.64 g, 2.1 mol) and tetrahydrofuran (2.5 L) were mixed, stirred to dissolve, heated to reflux for 3 h, and after the reaction was completed, cooled to room temperature, dimethylamine hydrochloride (342.47 g, 4.2 mol), trimethylamine hydrochloride (342.47 g, 4.2 mol) and dimethylamine hydrochloride (342.47 g, 4.2 mol) were added. Ethylamine (425.0 g, 4.2 mol) was heated to 35±5°C and reacted for 8 h. After the reaction was completed, the reaction solution was poured into 2 L of water, 3 L of ethyl acetate was added, and the mixture was stirred evenly. The pH value was adjusted to 3 with 6% hydrochloric acid, and the organic phase was discarded. The pH value of the aqueous phase was adjusted to 9 with a saturated sodium carbonate solution, and 3 L of ethyl acetate was added for extraction. The organic phase was retained, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine (compound 4, light yellow oil, 521.31 g, yield 96.40%).

[0093] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), isopropyl acetate (1 L) and acetone (1.5 L) were stirred and dissolved, cooled to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, stirred and crystallized at 0±5°C for 5 h, filtered and dried to obtain doxylamine succinate (698.35 g, yield 97.21%, HPLC purity 99.94%).

[0094] 1 H NMR (600MHz, DMSO-d6) δ: 12.57 (s, 2H, COOH), 8.48 (m, 1H, NH), 7.77 (m, 1H, Ar-H), 7.62 (d, 1H, Ar-H ,J=7.98), 7.35(d,2H,Ar-H,J=7.8), 7.28(t,2H,Ar-H,J=7.5), 7.20(m,2H,Ar-H), 3.40(m,2H,-CH 2 ), 2.67(m,2H,-CH2 ), 2.38(s,4H,-CH 2 ), 2.30(s,6H,-CH 3 ), 1.91(s,3H,-CH 3 ).

[0095] The DSC spectrum of doxylamine succinate is shown in Figure 3 , there is a sharp endothermic peak at about 105.15°C to 106.76°C, which is consistent with the doxylamine succinate crystal form A in CN105218433A. This indicates that the target crystal form is obtained in the present invention.

[0096] Example 2

[0097] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 1,2-bis(methylsulfonyloxy)ethane (458.33 g, 2.1 mol), cesium carbonate (684.22 g, 2.1 mol) and DMF (3 L) were mixed, stirred and dissolved, heated to 50 ° C for 5 h, and after the reaction was completed, cooled to room temperature, dimethylamine hydrochloride (342.47 g, 4.2 mol), N,N-diisopropyl ether were added; Amine (542.85 g, 4.2 mol), heated to 40 ± 5 ° C for 7 h; after the reaction is completed, the reaction solution is poured into 4 L of water, 4 L of isopropyl acetate is added, stirred evenly, the pH value is adjusted to 3 with 8% hydrochloric acid, the organic phase is discarded, the pH value of the aqueous phase is adjusted to 9 with saturated sodium carbonate solution, 5 L of 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 (compound 4, light yellow oil, 516.72 g, yield 95.55%).

[0098] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), ethyl acetate (2 L) and acetone (2 L) were stirred and dissolved, and the temperature was lowered to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, and the mixture was stirred and crystallized at 0±5°C for 5 h, filtered and dried to obtain doxylamine succinate (694.31 g, yield 96.65%, HPLC purity 99.9%).

[0099] Example 3

[0100] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 1,2-bis(methylsulfonyloxy)ethane (compound 3, 480.15 g, 2.2 mol), sodium tert-butoxide (211.42 g, 2.2 mol) and acetonitrile (3 L) were mixed, stirred and dissolved, heated to reflux for 3 h, and after the reaction was completed, cooled to room temperature, dimethylamine hydrochloride (342.47 g, 4.2 mol), triethylamine (300 g, 4.2 mol) were added. Amine (425.0 g, 4.2 mol), heated to 50±5°C and reacted for 6 h; after the reaction was completed, the reaction solution was poured into 3 L of water, 4 L of ethyl acetate was added, stirred evenly, the pH value was adjusted to 3 with 8% hydrochloric acid, the organic phase was discarded, the pH value of the aqueous phase was adjusted to 9 with saturated potassium carbonate solution, 4 L of ethyl acetate was added for extraction, the organic phase was retained, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine (compound 4, light yellow oil, 519.21 g, yield 96.01%).

[0101] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), ethyl acetate (2 L) and acetone (1.5 L) were stirred and dissolved, and the temperature was lowered to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, and the mixture was stirred and crystallized at 0±5°C for 4 h, filtered and dried to obtain doxylamine succinate (701.08 g, yield 97.59%, HPLC purity 99.9%).

[0102] Example 4

[0103] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 2-([tert-butoxycarbonyl]amino)ethyl p-toluenesulfonate (662.30 g, 2.1 mol), potassium tert-butoxide (235.64 g, 2.1 mol) and toluene (2.5 L) were mixed, stirred and dissolved, heated to about 110 ° C and refluxed for 3 h. After the reaction was completed, cooled to room temperature, 37% hydrochloric acid (404.02 g, 4.1 mol) was added, and the reaction was carried out at 50±5 ° C for 4 h. After the reaction was completed, To the reaction system, add paraformaldehyde solid (240.24 g, 8.0 mol) and 88% formic acid aqueous solution (836.91 g, 16.0 mol) by mass fraction, heat to about 110 ° C and reflux for 6 h; after the reaction is completed, pour the reaction solution into 2 L of water, stir evenly, separate the liquid, discard the organic phase, adjust the pH value of the aqueous phase to 9 with saturated potassium carbonate solution, add 2 L of ethyl acetate for extraction, retain the organic phase, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain doxylamine (compound 4, light yellow oil, 502.70 g, yield 92.96%).

[0104] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), ethyl acetate (1.5 L) and acetone (1.5 L) were stirred and dissolved, cooled to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, stirred and crystallized at 0±5°C for 4 h, filtered and dried to obtain doxylamine succinate (692.86 g, yield 96.45%, HPLC purity 99.93%).

[0105] 1 H NMR (600MHz, DMSO-d6) δ: 12.57 (s, 2H, COOH), 8.48 (m, 1H, NH), 7.78 (m, 1H, Ar-H), 7.62 (d, 1H, Ar-H, J=7.98), 7.37(d,2H,Ar-H,J=7.74), 7.28(t,2H,Ar-H,J=7.56), 7.22(m,2H,Ar-H), 3.40(m,2H,-CH 2 ), 2.67(m,2H,-CH 2 ), 2.38(s,4H,-CH 2 ), 2.30(s,6H,-CH 3 ), 1.91(s,3H,-CH 3 ).

[0106] The DSC spectrum of doxylamine succinate is shown in Figure 6 , there is a sharp endothermic peak at about 104.54°C to 106.59°C, which is consistent with the doxylamine succinate crystal form A in CN105218433A. This indicates that the target crystal form is obtained in the present invention.

[0107] Example 5

[0108] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 2-([tert-butoxycarbonyl]amino)ethyl methanesulfonate (502.51 g, 2.1 mol), potassium tert-butoxide (235.64 g, 2.1 mol) and DMF (3 L) were mixed, stirred and dissolved, heated to 100 ° C for 3 h, and after the reaction was completed, cooled to room temperature, 88% formic acid aqueous solution (214.46 g, 4.1 mol) was added, and the reaction was carried out at 40 ° C for 4 h. After the reaction was completed, the reaction system was added. Add paraformaldehyde solid (240.24 g, 8.0 mol) and 88% formic acid aqueous solution (732.30 g, 14.0 mol) by mass fraction, heat to 100 ° C and react for 8 h; after the reaction is completed, pour the reaction solution into 3 L of water, add 4 L of isopropyl acetate, stir evenly, separate the liquids, discard the organic phase, adjust the pH value of the aqueous phase to 9 with saturated sodium carbonate solution, add 3 L of isopropyl acetate to extract, retain the organic phase, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain doxylamine (compound 4, light yellow oil, 506.13 g, yield 93.60%).

[0109] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), isopropyl acetate (1.5 L) and acetone (2 L) were stirred and dissolved, cooled to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, stirred and crystallized at 0±5°C for 6 h, filtered and dried to obtain doxylamine succinate (695.14 g, yield 96.77%, HPLC purity 99.8%).

[0110] Example 6

[0111] Step 1: Under nitrogen protection, 1-phenyl-1-(pyridin-2-yl)-1-ethanol (compound 2, 398.5 g, 2.0 mol), 2-([tert-butyloxycarbonyl]amino)ethyl methanesulfonate (526.44 g, 2.2 mol), sodium tert-butoxide (211.42 g, 2.2 mol) and dimethyl sulfoxide (3 L) were mixed, stirred and dissolved, heated to 105 ° C for 3 h, and after the reaction was completed, cooled to room temperature, trifluoroacetic acid (501.69 g, 4.4 mol) was added, and the reaction was carried out at 50 ° C for 3 h. After the reaction was completed, the reaction system was added with poly (vinyl alcohol) 2-nitropropene; Formaldehyde solid (240.24 g, 8.0 mol) and 88% formic acid aqueous solution (679.99 g, 13.0 mol) were heated to 105 ° C for 9 hours; after the reaction was completed, the reaction solution was poured into 3L of water, 4L of ethyl acetate was added, stirred evenly, separated, and the organic phase was discarded. The pH value of the aqueous phase was adjusted to 9 with a saturated potassium carbonate solution, and 4L of ethyl acetate was added for extraction. The organic phase was retained, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain doxylamine (compound 4, light yellow oil, 514.48 g, yield 95.14%).

[0112] Step 2: At room temperature, doxylamine (compound 4, 500.0 g, 1.849 mol), isopropyl acetate (2 L) and acetone (1.5 L) were stirred and dissolved, cooled to 0±5°C, succinic acid (218.35 g, 1.849 mol) was added thereto, stirred and crystallized at 0±5°C for 5 h, filtered and dried to obtain doxylamine succinate (693.87 g, yield 96.59%, HPLC purity 99.8%).

Claims

1. A method for preparing doxylamine succinate, characterized in that: The synthetic route is as follows: Wherein, R1 and R2 are independently selected from fluorine, chlorine, bromine, iodine, R3 is selected from methyl, p-methylphenyl; or Wherein, R is selected from fluorine, chlorine, bromine, iodine, R3 is selected from methyl, p-methylphenyl; The following steps are involved: Step 1, method 1: 1-phenyl-1-(pyridin-2-yl)-1-ethanol and formula The substituted ethane derivatives shown are used as raw materials, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and the substituted ethane derivatives are dissolved in an organic solvent under the protection of nitrogen or inert gas, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and the substituted ethane derivatives undergo a substitution reaction under the action of an alkaline reagent, and then a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride is added in the presence of an acid binding agent to react; after the reaction is completed, doxylamine is obtained by post-treatment; Or method 2: 1-phenyl-1-(pyridin-2-yl)-1-ethanol and formula The N-(tert-butoxycarbonyl)-2-ethylamine derivative shown is used as a raw material, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and N-(tert-butoxycarbonyl)-2-ethylamine derivative are dissolved in an organic solvent under the protection of nitrogen or inert gas, 1-phenyl-1-(pyridin-2-yl)-1-ethanol and N-(tert-butoxycarbonyl)-2-ethylamine derivative undergo substitution reaction under the action of an alkali reagent, and then a deprotection reaction is carried out under acidic conditions to remove the Boc protecting group, and a methylating agent is added to carry out a methylation reaction; after the reaction is completed, doxylamine is obtained through post-treatment; the methylating agent is paraformaldehyde and formic acid; Step 2: Doxylamine and succinic acid undergo a salt-forming reaction in an organic solvent to obtain doxylamine succinate.

2. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1 of method 1, the molar ratio of 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the substituted ethane derivative is 1:1.0 to 1:1.5, preferably 1:1.0 to 1:1.2, and more preferably 1:1.05 to 1:1.1; R1, R2 are independently selected from bromine, iodine, sulfonate R3 is selected from methyl, p-methylphenyl; preferably, R1=R2=sulfonate R3 is selected from methyl, p-methylphenyl; In step 1 of method 2, the molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the N-(tert-butyloxycarbonyl)-2-ethylamine derivative is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.2, and more preferably 1:1.05 to 1:1.1; R is selected from bromine, iodine, sulfonate R3 is selected from methyl, p-methylphenyl; preferably, R is selected from sulfonate R3 is selected from methyl and p-methylphenyl.

3. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1 of method 1, the molar ratio of the 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, and more preferably 1:1.05 to 1:1.1; 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, cesium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine; In step 1 of method 2, 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, and more preferably 1:1.05 to 1:1.1; 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, cesium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine.

4. The preparation method of doxylamine succinate according to claim 1, characterized in that: In step 1 of method 1, the organic solvent is selected from one or more of toluene, xylene, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide, preferably tetrahydrofuran, acetonitrile, and N,N-dimethylformamide; In step 1 of method 2, the organic solvent is selected from one or more of methyltetrahydrofuran, acetonitrile, toluene, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, and dioxane, preferably one or two of toluene, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

5. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1 of method 1, the temperature of the substitution reaction is 20° C. to the reflux temperature of the organic solvent, preferably 30 to 90° C.; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours; After the substitution reaction is completed, the mixture is cooled to room temperature, a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride and an acid binding agent are added, and the temperature is raised to 20 to 80° C. for reaction for 1 to 12 hours; preferably, after the substitution reaction is completed, the mixture is cooled to room temperature, a tetrahydrofuran solution of dimethylamine or dimethylamine hydrochloride and an acid binding agent are added, and the temperature is raised to 30 to 60° C. for reaction for 5 to 8 hours; The molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to dimethylamine or its hydrochloride is 1:1.0 to 1:8.0, preferably 1:2.0 to 1:4.0; the molar ratio of the 1-phenyl-1-(pyridin-2-yl)-1-ethanol to the acid binding agent is 1:1.0 to 1:8.0, preferably 1:2.0 to 1:4.0; The acid binding agent is an organic base; the organic base is selected from at least one of triethylamine and N,N-diisopropylethylamine.

6. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1 of method 1, the post-treatment is as follows: after the reaction is completed, water is added to the reaction solution according to a volume ratio of organic solvent to water of 0.75:1 to 1.25:1, 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 a saturated sodium carbonate solution or a 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, and concentrated to obtain doxylamine; Preferably, when the reaction solvent is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide, after the reaction is completed, water is added to the reaction solution at a volume ratio of 0.75:1 to 1.25:1 for the organic solvent and water, ethyl acetate or isopropyl acetate is added as an extraction solvent at a volume ratio of 0.6:1 to 1:1 for the organic solvent and extraction solvent, 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 a saturated sodium carbonate solution or a saturated potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain doxylamine.

7. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1 of method 2, the temperature of the substitution reaction is 40° C. to 150° C., preferably 60° C. to 110° C.; the time of the substitution reaction is 1 to 12 hours, preferably 3 to 5 hours; After the substitution reaction is completed, the mixture is cooled to room temperature, an acid is added, and the mixture is heated under acidic conditions to perform a deprotection reaction to remove the Boc protecting group; after the reaction is completed, paraformaldehyde and formic acid are added to the reaction system to perform a methylation reaction; The acid is selected from concentrated hydrochloric acid, formic acid or trifluoroacetic acid; the temperature of the deprotection reaction is 20 to 80° C., preferably 30 to 60° C.; the time of the deprotection reaction is 1 to 12 hours, preferably 2 to 5 hours; The temperature of the methylation reaction is 50 to 150° C., preferably 80 to 115° C.; the time of the methylation reaction is 1 to 12 hours, preferably 6 to 10 hours; The molar ratio of the paraformaldehyde to 1-phenyl-1-(pyridin-2-yl)-1-ethanol is 2:1 to 16:1, preferably 3:1 to 5:1; The molar ratio of formic acid to 1-phenyl-1-(pyridin-2-yl)-1-ethanol is 3:1 to 32:1, preferably 4.5:1 to 10:1, and more preferably 6.5:1 to 8:

1.

8. The method for preparing doxylamine succinate according to claim 1, wherein: In step 1 of method 2, the post-treatment is as follows: adding water to the reaction solution according to a volume ratio of organic solvent to water of 0.75:1 to 1.25:1, adjusting the pH value to 3 to 4 with 6% to 10% hydrochloric acid, discarding the organic phase, adjusting the pH value of the aqueous phase to 8 to 9 with a saturated sodium carbonate or potassium carbonate solution, adding ethyl acetate or isopropyl acetate for extraction, retaining the organic phase, and drying the organic phase over anhydrous sodium sulfate and concentrating to obtain doxylamine; Preferably, when the reaction solvent is N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide, after the methylation reaction is completed, water is added to the reaction solution according to a volume ratio of the reaction solvent to water of 0.75:1 to 1.25:1, ethyl acetate or isopropyl acetate is added as an extraction solvent according to a volume ratio of the reaction solvent to the 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 a saturated sodium carbonate or potassium carbonate solution, ethyl acetate or isopropyl acetate is added for extraction, the organic phase is retained, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain doxylamine.

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; 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 4 to 6 hours.

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 more of acetone, acetonitrile, ethyl acetate, isopropyl acetate, isopropanol, ethanol, and methanol, preferably a mixed solvent of acetone and one selected from ethyl acetate and isopropyl acetate in a volume ratio of 4:1 to 1:4.

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