Synthesis and purification method of roxatidine acetate hydrochloride

Abstract

The present invention relates to a synthesis and purification method of roxatidine acetate hydrochloride, and belongs to the technical field of pharmaceutical chemistry. The present invention provides a purification method of roxatidine acetate hydrochloride, using N, N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent for recrystallization. In addition, the present invention also provides a preparation method of roxatidine acetate. Experimental results show that, using the synthesis and purification method of roxatidine acetate hydrochloride provided by the present invention, the total yield reaches 57.1%, which is higher than the existing level, and the impurity level of the obtained roxatidine acetate hydrochloride is significantly reduced, the product quality is not lower than the original research drug level, and has obvious advantages compared with similar products, and the product safety, effectiveness, and quality controllability are improved as a whole, meeting the consistency evaluation requirements.

Description

Technical Field

[0001] The invention relates to a synthesis and purification method of roxatidine acetate hydrochloride, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Roxatidine acetate hydrochloride, chemical name is 2-acetoxy-N-[3-[3-(1-piperidinylmethyl) phenoxy] propyl] acetamide hydrochloride, first launched in Japan by Imperial Organ Company in August 1986, is a new generation of selective histamine H 2 Receptor antagonist. This product is rapidly converted into the active metabolite roxatidine after deacetylation by hydrolysis in the body, which can inhibit the gastric acid secretion caused by histamine, pentagastrin, and M cholinergic receptor agonists in animals and humans, and can also inhibit the secretion of basal gastric acid and the nocturnal gastric acid secretion caused by other factors such as food. It is mainly used to prevent and treat digestive system diseases caused by high secretion of gastric acid, such as gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.

[0003] Roxatidine acetate hydrochloride is easy to degrade. For example, the acetate in its structure is easy to degrade under the action of acid, alkali, water, etc. to produce impurity roxatidine, and the impurities generated during the synthesis process lead to low purity of the raw material drug. The maximum single impurity of the original drug reference preparation is 0.27%. If the synthesis process provided by Synthetic Communications is followed, the purity of the final product can only reach 98.5% (see: A New Synthesis of Roxatidine Acetate. SYNTHETIC COMMUNICATIONS, 29 (1), 15-20, 1999). Therefore, it is necessary to better control the content of related substances in roxatidine acetate hydrochloride.

[0004] In addition, most of the existing synthesis processes of roxatidine acetate hydrochloride have problems such as long reaction time, high temperature, complex operation, and low yield. After reviewing the literature, there are currently three main synthesis routes:

[0005] Route 1 (see: Zhou Zhihua, Lei Pengfei, Xu Binghao, et al., Synthesis process optimization and preliminary quality study of roxatidine acetate hydrochloride [J], Zhongnan Pharmacy, Vol. 18, No. 2, February 2020: 205-209)

[0006]

[0007] The route uses m-hydroxybenzaldehyde and piperidine to react under the action of potassium borohydride, an explosive-making reagent, to prepare 3-(1-piperidinylmethyl)phenol, then reacts with 3-chloropropylamine hydrochloride under the action of sodium hydroxide and toluene to obtain 3-(3-piperidin-1-ylmethylphenoxy)propylamine, and then reacts with chloroacetyl chloride to obtain 2-chloro-N-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide, and further reacts with potassium acetate to obtain roxatidine acetate, and then uses hydrogen chloride and ethyl acetate to form salt and then uses ethanol and ethyl acetate to refine to obtain roxatidine acetate hydrochloride. In its step 1, potassium borohydride, an explosive-making reagent, is used, and the post-processing is complicated and the yield is low (88.6%); the reaction speed in step 2 is very slow and the conversion rate is low; the reaction temperature in step 4 is high, the post-processing operation mode is complicated, and the impurity roxatidine is easily generated, which is not easy to purify and remove; in step 5, during the purification and refining process, roxatidine acetate hydrochloride is easily degraded to produce the impurity roxatidine. Therefore, this route has high production cost, low total yield (31.0%), complex operation and is not suitable for industrial production.

[0008] Route 2 (see: Xu Wei et al., A Synthesis Method of Roxatidine Acetate Hydrochloride [P], CN 103058958)

[0009]

[0010] This route increases the types of materials when preparing M2, and M2 needs to be purified by distillation, which requires high production equipment. M4 is prepared by reacting with glycolic acid. Experiments have found that if this step is reacted at 90±5℃ as recorded in the literature, the conversion rate is low and the reaction is slow. It is better to react at a high temperature above 140℃. In step 5, the degradation impurity roxatidine is easily produced during the preparation of API. Therefore, this route is not suitable as a commercial production process.

[0011] Route 3 (see: Guo Rongyao, Wang Xiaofeng, et al., A new method for preparing 3-(1-piperidinylmethyl)phenol, an intermediate of roxatidine acetate hydrochloride [P], CN107698538)

[0012]

[0013] Step 1 of this route requires the use of potassium iodide for catalytic reaction, and the reaction temperature is 90-110°C for 20 hours, the reaction temperature is high, and the reaction time is long; the reaction temperature of step 2 is 160-165°C, and the reaction temperature is high; the reaction temperature of step 5 is reflux, the temperature is relatively high, and the post-treatment requires water washing, concentration and other treatments, the operation is complicated, and it is easy to hydrolyze again to generate roxatidine during the concentration process; finally, it is dissolved in acetone and then dripped with hydrogen chloride ethyl acetate solution to form salt at low temperature. The raw material has no refining step, which is not conducive to production in the raw material workshop. Therefore, this route is not suitable as a commercial route.

[0014] In order to solve the problems existing in the above process, such as long reaction time, high temperature, complicated operation, low yield, easy degradation of raw materials during the production process, and low product purity, it is urgent to develop a synthesis and purification method that is more suitable for industrial production and can prepare high-purity roxatidine acetate hydrochloride. Summary of the invention

[0015] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the first object of the present invention is to provide a method for refining roxatidine acetate hydrochloride. The second object of the present invention is to provide a method for preparing roxatidine acetate hydrochloride. The third object of the present invention is to provide a method for preparing roxatidine acetate hydrochloride.

[0016] The invention provides a method for refining roxatidine acetate hydrochloride, which uses N,N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent for recrystallization.

[0017] Furthermore, the refining method comprises the following steps:

[0018] a. Adding a good solvent: mixing crude roxatidine acetate hydrochloride and N,N-dimethylformamide, heating and dissolving, wherein the mass ratio of crude roxatidine acetate hydrochloride to N,N-dimethylformamide is 1:(4-10); preferably, the mass ratio of crude roxatidine acetate hydrochloride to N,N-dimethylformamide is 1:6;

[0019] b. Adding a poor solvent: adding isopropyl acetate to the solution obtained in step a, cooling to -10 to 40° C. to precipitate roxatidine acetate hydrochloride, collecting the material, and obtaining a refined roxatidine acetate hydrochloride, wherein the mass ratio of crude roxatidine acetate hydrochloride: isopropyl acetate is 1:(4 to 10); preferably, cooling to 0 to 10° C. to precipitate roxatidine acetate hydrochloride; preferably, the mass ratio of crude roxatidine acetate hydrochloride: isopropyl acetate is 1:6.

[0020] Furthermore, the refining method satisfies at least one of the following:

[0021] Step a: heating to 50-80°C to dissolve;

[0022] Preferably, step a is heated to 50-60° C. to dissolve;

[0023] Step a: heating and dissolving, followed by hot filtration;

[0024] Step b: adding isopropyl acetate in batches: first cooling to 30-40° C., adding 0.4-0.6 times the mass of the crude roxatidine acetate hydrochloride, adding seed crystals, stirring evenly, and then continuing to add the remaining isopropyl acetate, cooling to 0-10° C. to precipitate roxatidine acetate hydrochloride;

[0025] Preferably, 0.05-5% of seed crystals are added based on the mass of the crude roxatidine acetate hydrochloride;

[0026] Preferably, 0.1-2% of seed crystals are added based on the mass of the crude roxatidine acetate hydrochloride;

[0027] Preferably, 0.5-1.5% of seed crystals are added based on the mass of the crude roxatidine acetate hydrochloride;

[0028] Preferably, 1% of seed crystals are added based on the mass of the crude roxatidine acetate hydrochloride;

[0029] Preferably, the crystallization is stirred at 0-10°C for more than 1 hour;

[0030] Preferably, the crystallization is stirred at 0 to 10° C. for 1.5 to 2.5 hours.

[0031] The invention provides a method for preparing roxatidine acetate. Roxatidine and acetic anhydride are used as raw materials, and isopropyl acetate as a reaction solvent is added to react at 10-50° C. to generate roxatidine acetate. The mass ratio of roxatidine hemioxalate to acetic anhydride is 3.5: (1.0-6.2) based on the mass of roxatidine hemioxalate.

[0032] Furthermore, the preparation method satisfies at least one of the following:

[0033] React at 40-50°C;

[0034] Based on the mass of roxatidine hemioxalate, the mass ratio of roxatidine hemioxalate to acetic anhydride is 3.5:(4.0-4.6);

[0035] Reaction time 1.5 to 2.5 hours;

[0036] Preferably, the reaction time is 2.0 hours;

[0037] Based on the mass of roxatidine hemioxalate, add 4 to 5 times the reaction solvent isopropyl acetate;

[0038] The post-reaction treatment is to add an acetic anhydride quenching solvent or a mixed solvent of an acetic anhydride quenching solvent and isopropyl acetate, and stir evenly; wherein the acetic anhydride quenching solvent is selected from a lower alcohol;

[0039] Preferably, the acetic anhydride quenching solvent is selected from at least one of methanol, ethanol, isopropanol and n-propanol.

[0040] Further, roxatidine is prepared by the following method:

[0041] Step A: Compound M1, 3-chloropropylamine or its salt and a base are reacted in N,N-dimethylformamide to obtain intermediate M2:

[0042]

[0043] Step B: Intermediate M2 reacts with acetoxyacetyl chloride to obtain intermediate M3:

[0044]

[0045] Step C: hydrolyze the intermediate M3 to obtain the crude roxatidine M4:

[0046]

[0047] Step D: The crude roxatidine M4 is salified with oxalic acid to obtain the intermediate M5:

[0048]

[0049] Step E: The intermediate M5 reacts with a base to obtain the refined roxatidine M6:

[0050]

[0051] Furthermore, the preparation method satisfies at least one of the following:

[0052] The alkali described in step A is sodium hydroxide;

[0053] The reaction temperature of step A is 30-70°C;

[0054] Preferably, the reaction temperature of step A is 60-70°C;

[0055] The reaction time of step A is 1.2 to 1.8 hours;

[0056] After the reaction in step A is completed, the reaction solution is extracted with an organic solvent to obtain a solution of intermediate M2, which is then transferred to step B without purification;

[0057] Preferably, the organic solvent used to extract the reaction solution in step A is selected from at least one of dichloromethane, chloroform, ethyl acetate, isopropyl acetate and toluene;

[0058] Adding an acid binding agent to the reaction system of step B;

[0059] Preferably, the acid binding agent is triethylamine;

[0060] The reaction solvent of step B is dichloromethane;

[0061] The reaction temperature of step B is -10 to 45°C;

[0062] Preferably, the reaction temperature of step B is 10-20°C;

[0063] After the reaction in step B is completed, the reaction solution is subjected to solid-liquid separation, the liquid phase is collected and concentrated to obtain intermediate M3, which is then transferred to step C without purification;

[0064] Step C is subjected to alkaline hydrolysis;

[0065] Preferably, in step C, sodium hydroxide is added for alkaline hydrolysis;

[0066] The reaction solvent of step C is ethanol or a mixed solvent of ethanol and water;

[0067] The reaction temperature of step C is -10 to 45°C;

[0068] Preferably, the reaction temperature of step C is 30-40°C;

[0069] After the reaction in step C is completed, the reaction solution is extracted with an organic solvent and concentrated to obtain a crude roxatidine product M4, which is then transferred to step D without purification;

[0070] Preferably, the organic solvent used to extract the reaction solution in step C is selected from at least one of toluene, ethyl acetate, dichloromethane, chloroform, and isopropyl acetate;

[0071] The reaction solvent in step D is selected from at least one of methanol, ethanol and isopropanol;

[0072] The reaction temperature of step D is 20 to 90°C;

[0073] Preferably, the reaction temperature of step D is 75-85°C;

[0074] After the reaction in step D is completed, the temperature is lowered to 15-25°C for crystallization;

[0075] Step D comprises recrystallizing the intermediate M5, wherein the recrystallization solvent is a mixed solvent of at least one of methanol, ethanol, and isopropanol and water;

[0076] Preferably, the recrystallization solvent is 85% w / w ethanol aqueous solution;

[0077] In step D, 0.05% to 5% seed crystals are added during the recrystallization process based on the mass of compound M1;

[0078] Preferably, based on the mass of compound M1, 0.1% to 2% seed crystals are added during the recrystallization process in step D;

[0079] Preferably, based on the mass of compound M1, 0.5% to 1.5% seed crystals are added during the recrystallization process in step D;

[0080] Preferably, based on the mass of compound M1, 1% seed crystals are added during the recrystallization process in step D;

[0081] The oxalic acid in step D can be replaced by at least one of hydrochloric acid, methanesulfonic acid, and tartaric acid;

[0082] The base described in step E is potassium hydroxide;

[0083] The reaction solvent of step E is water;

[0084] The reaction temperature of step E is -10 to 45°C;

[0085] Preferably, the reaction temperature of step E is 10-20°C;

[0086] After the reaction in step E is completed, the reaction solution is extracted with an organic solvent and concentrated to obtain roxatidine refined product M6;

[0087] Preferably, the organic solvent used to extract the reaction solution in step E is selected from at least one of toluene, ethyl acetate, dichloromethane, chloroform, and isopropyl acetate;

[0088] Control the moisture content of roxatidine refined product M6 to less than 6%;

[0089] Preferably, the moisture content of the refined roxatidine product M6 is controlled to be less than 4%.

[0090] Further, compound M1 is prepared by the following steps F:

[0091]

[0092] m-Hydroxybenzaldehyde and piperidine react in formic acid to prepare compound M1.

[0093] Furthermore, the preparation method satisfies at least one of the following:

[0094] In step F, the mass ratio of hydroxybenzaldehyde to piperidine is 1:(1.5-5.0);

[0095] Preferably, the mass ratio of hydroxybenzaldehyde to piperidine in step F is 1:2.43;

[0096] In step F, the mass ratio of hydroxybenzaldehyde to formic acid is 1:(1.0-10.0);

[0097] Preferably, the mass ratio of hydroxybenzaldehyde to formic acid in step F is 1:5.0;

[0098] The reaction temperature of step F is 80-140°C;

[0099] Preferably, the reaction temperature of step F is 120-140°C;

[0100] The reaction time of step F is 1.2 to 1.8 hours;

[0101] Step F: post-reaction treatment is to adjust the pH to 8.0-12.0 to precipitate compound M1;

[0102] Preferably, in step F, the pH is adjusted to 10.0 to 11.0 at the end point of the post-reaction treatment;

[0103] Preferably, based on the mass of m-hydroxybenzaldehyde, 0.05% to 5% of seed crystals are added in the post-reaction treatment of step F to precipitate compound M1;

[0104] Preferably, based on the mass of m-hydroxybenzaldehyde, 0.1% to 2% of seed crystals are added in the post-reaction treatment of step F to precipitate compound M1;

[0105] Preferably, based on the mass of m-hydroxybenzaldehyde, 0.5% to 1.5% of seed crystals are added in the post-reaction treatment of step F to precipitate compound M1;

[0106] Preferably, based on the mass of m-hydroxybenzaldehyde, 1% seed crystals are added in the post-reaction treatment of step F to precipitate compound M1.

[0107] The invention provides a method for preparing roxatidine acetate hydrochloride, comprising the following steps: obtaining roxatidine acetate according to the preparation method, converting the roxatidine acetate into hydrochloride, and finally obtaining a refined roxatidine acetate hydrochloride according to the refining method.

[0108] Furthermore, the preparation of roxatidine acetate into hydrochloride comprises the following steps: adding hydrogen chloride to an isopropyl acetate solution of roxatidine acetate to precipitate roxatidine acetate hydrochloride, and collecting the material to obtain the product.

[0109] Furthermore, the method for converting roxatidine acetate into hydrochloride satisfies at least one of the following:

[0110] Add hydrogen chloride at 0-45°C;

[0111] Preferably, hydrogen chloride is added at 10-20°C;

[0112] Hydrogen chloride is added in the form of a solution of hydrogen chloride in isopropyl acetate;

[0113] Preferably, the hydrogen chloride content in the isopropyl hydrogen chloride acetate solution is 4.0-4.3%;

[0114] Preferably, the isopropyl hydrochloride acetate solution is added in batches: based on the mass of roxatidine oxalate, 0.2 to 0.3 times the isopropyl hydrochloride acetate solution is first added, seed crystals are added, and after stirring evenly, 2 to 3 times the isopropyl hydrochloride acetate solution is continued to be added to precipitate roxatidine acetate hydrochloride;

[0115] Preferably, 0.05% to 5% of seed crystals are added based on the mass of roxatidine oxalate;

[0116] Preferably, 0.1% to 2% of seed crystals are added based on the mass of roxatidine oxalate;

[0117] Preferably, 0.5% to 1.5% of seed crystals are added based on the mass of roxatidine oxalate;

[0118] Preferably, 1% of seed crystals are added based on the mass of roxatidine oxalate;

[0119] After the addition of hydrogen chloride is complete, the mixture is stirred and crystallized for 1.0 to 1.5 hours.

[0120] The synthesis and purification method of roxatidine acetate hydrochloride provided by the present invention has at least the following beneficial effects:

[0121] 1. A refining method suitable for the industrial production of roxatidine acetate hydrochloride has been developed, which effectively improves the product purity (99.95%) and reduces the impurity level (single impurity <0.05%). The relevant substances, content, melting point, ignition residue, microorganisms, endotoxins, solvent residues, etc. of the roxatidine acetate hydrochloride raw material produced by the refining method of the present invention all comply with the relevant ICH guidelines and meet the JP standards.

[0122] 2. The synthesis process provided by the present invention shortens the reaction time as a whole, improves the production efficiency, and the reaction conditions are milder and more controllable. Specifically: the reaction time for preparing M1 is short (within 2 hours) and the yield is high (more than 97%); the reaction temperature for preparing M2 is low (below 70°C) and the reaction time is short (within 2 hours); the reaction temperature for preparing M4 is low (below 45°C) and the reaction time is short (30 minutes); the reaction temperature for preparing M7 is low (below 50°C) and the reaction speed is fast (within 2.5 hours).

[0123] 3. The intermediates M2-M5 are optimized through continuous process design, which greatly simplifies the post-processing operation, further improves the yield and production efficiency, and reduces the production cost.

[0124] 4. The total yield of the synthesis process provided by the present invention reaches 57.1% (based on m-hydroxybenzaldehyde), which is higher than the existing level, and the impurity level of the prepared roxatidine acetate hydrochloride is significantly reduced. The product quality is not lower than the level of the original drug (the maximum single impurity of the reference preparation is 0.27%). Compared with similar products, it has obvious advantages, and the product safety, effectiveness, and quality controllability are improved as a whole, meeting the requirements of consistency evaluation.

[0125] 5. After step-by-step amplification and final process verification on a 15 kg batch, it was proved that the synthesis process of roxatidine acetate hydrochloride provided by the present invention is stable and has the potential for further stable amplification of production. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] Figure 1 is the HPLC spectrum of the intermediate M1 in Example 1;

[0127] Figure 2 is the HPLC spectrum of the intermediate M5 in Example 1;

[0128] Figure 3 The HPLC spectrum of the final product roxatidine acetate hydrochloride in Example 1;

[0129] Figure 4 The TGA-DSC spectrum of the final product roxatidine acetate hydrochloride in Example 1;

[0130] Figure 5 The XRD spectrum of the final product roxatidine acetate hydrochloride in Example 1;

[0131] Figure 6 It is the HPLC spectrum of the final product roxatidine acetate hydrochloride in the comparative example. DETAILED DESCRIPTION

[0132] In a first aspect, the present invention provides a method for purifying roxatidine acetate hydrochloride, wherein N,N-dimethylformamide is used as a good solvent and isopropyl acetate is used as a poor solvent for recrystallization.

[0133] The above technical scheme is obtained based on the following findings of the inventors: Roxatidine acetate hydrochloride is easily degraded. For example, the acetate in its structure is easily degraded under the action of acid, alkali, water, etc. to produce the impurity roxatidine, and the impurities generated during the synthesis process, resulting in low purity of the raw material drug. The maximum single impurity of the original drug reference preparation is 0.27%. If the synthesis process provided by Synthetic Communications is followed, the purity of the final product can only reach 98.5% (see: A New Synthesis of Roxatidine Acetate. SYNTHETIC COMMUNICATIONS, 29 (1), 15-20, 1999). Therefore, it is necessary to further control the level of related substances of roxatidine acetate hydrochloride. In addition, when the prior art refines the product, ethanol needs to be heated to 60°C for recrystallization (see route 1 in the background technology). However, the inventors found through comparative experiments that when ethanol and methanol are used as recrystallization solvents, roxatidine acetate hydrochloride is easily degraded to produce impurities such as roxatidine, resulting in poor product quality stability and further increase in impurity levels. After investigation, the present invention creatively selects N,N-dimethylformamide and isopropyl acetate as recrystallization solvents, thereby being able to produce a refined product of roxatidine acetate hydrochloride with a purity of up to 99.95% and a single impurity of <0.05%, which significantly improves the product purity and reduces the impurity level.

[0134] In a second aspect, the present invention provides a method for preparing roxatidine acetate, wherein roxatidine and acetic anhydride are used as raw materials, isopropyl acetate is added as a reaction solvent, and the reaction is carried out at 10 to 50° C. to generate roxatidine acetate; wherein, based on the mass of roxatidine hemioxalate, the mass ratio of roxatidine hemioxalate to acetic anhydride is 3.5:(1.0 to 6.2).

[0135] The above technical scheme is obtained based on the following discovery of the inventor: when the existing synthesis process prepares roxatidine acetate via roxatidine, it is necessary to either react at a higher temperature (acetic acid reflux, see route 3), or reduce the reaction temperature but extend the reaction time (5 hours, see route 2), which is not conducive to reducing production costs and improving production efficiency. The present invention optimizes the process conditions of this step, especially selects a suitable reaction solvent and acetic anhydride dosage, thereby fully reacting at a lower reaction temperature and in a shorter time; moreover, under the process conditions adopted by the present invention, the reaction is more complete and clean, so that the post-processing is simplified, and the reaction is added after the reaction is completed. The acetic anhydride quenching solvent can directly carry out the next step of the hydrochloride reaction, without the need for the existing process to carry out the complex post-processing procedures such as concentration, washing, alkali adjustment, extraction, sodium sulfate drying, filtration, and re-concentration, and it also helps to avoid the product roxatidine acetate from being hydrolyzed during post-processing.

[0136] In the third aspect, the present invention provides a method for preparing roxatidine acetate hydrochloride, comprising the following steps: preparing roxatidine acetate according to the preparation method described in the second aspect, then converting roxatidine acetate into hydrochloride, and finally obtaining a refined roxatidine acetate hydrochloride product according to the purification method described in the first aspect. Thus, high-purity (99.95%, single impurity <0.05%) roxatidine acetate hydrochloride can be obtained with a high total yield (57.1%), and the raw material drug related substances, content, melting point, ignition residue, microorganisms, endotoxins, solvent residues, etc. all comply with the relevant ICH guidelines and JP standards; the reaction process temperature is easy to control, the post-processing operation is simple, and it is easy to industrialize production.

[0137] The present invention may also have the following additional technical features:

[0138] In some specific embodiments of the present invention, roxatidine is prepared by the following method:

[0139] Step A: Compound M1, 3-chloropropylamine or its salt and a base are reacted in N,N-dimethylformamide to obtain intermediate M2:

[0140]

[0141] Step B: Intermediate M2 reacts with acetoxyacetyl chloride to obtain intermediate M3:

[0142]

[0143] Step C: hydrolyze the intermediate M3 to obtain the crude roxatidine M4:

[0144]

[0145] Step D: The crude roxatidine M4 is salified with oxalic acid to obtain the intermediate M5:

[0146]

[0147] Step E: The intermediate M5 reacts with a base to obtain the refined roxatidine M6:

[0148]

[0149] In the preparation of 3-(3-piperidin-1-ylmethylphenoxy)propylamine (intermediate M2), the present invention compares solvents such as toluene, N,N-dimethylformamide, and dimethyl sulfoxide, and finds that toluene has poor solubility in materials, which seriously affects the reaction rate, or requires reaction at high temperature, and the conversion rate is low; dimethyl sulfoxide is easily decomposed under the action of strong alkali and is not easy to stir. This step preferably uses N,N-dimethylformamide as the reaction solvent. After optimization, the reaction temperature for preparing intermediate M2 is low, the reaction time is short, and the conversion rate is high.

[0150] When preparing roxatidine, a synthetic route is adopted in which acetoxyacetyl chloride is first reacted with intermediate M2 to obtain crude roxatidine acetate (intermediate M3), and then hydrolyzed to obtain crude roxatidine M4, thereby achieving the preparation of roxatidine at a lower temperature (route 3: 160-165°C).

[0151] In some specific embodiments, the present invention optimizes the post-treatment method for preparing intermediate M2. Without further purification, the dichloromethane solution of intermediate M2 is directly subjected to the next step reaction, avoiding the high-temperature distillation operation as in Route 2. The post-treatment is simpler and more suitable for industrial production.

[0152] In some specific embodiments, the present invention adopts a telescopic process, and M2-M5 is produced without separation and purification, which greatly simplifies subsequent operations, improves the yield and production efficiency, reduces production costs, and has a single solvent, which is convenient for recycling and highlighting the green and environmentally friendly characteristics of the process.

[0153] In some specific embodiments of the present invention, the post-treatment of the intermediate M6 uses purified water to wash the reaction solution, avoids the use of anhydrous sodium sulfate for drying, reduces the generation of solid waste, and greatly reduces the risk of the burning residue of the raw material drug exceeding the limit. The QbD (Quality by Design) concept is integrated into the research and development process of the raw material drug, and process control is performed on each key quality attribute of the raw material drug.

[0154] In some specific embodiments of the present invention, compound M1 is prepared by the following steps F:

[0155]

[0156] m-Hydroxybenzaldehyde and piperidine react in formic acid to prepare compound M1.

[0157] In the preparation of compound M1, the present invention compared potassium borohydride, sodium borohydride and formic acid, and found that the formic acid reaction had fewer impurities and was easier to control.

[0158] In some specific embodiments, the present invention optimizes the amount of piperidine, which helps to shorten the reaction time.

[0159] In some specific embodiments, the present invention optimizes the post-treatment method of step F, and adjusts the pH while using seed crystals to induce crystallization and precipitate solids. The pH adjuster can be an inorganic base such as ammonia water, sodium hydroxide, potassium hydroxide, or an organic base such as triethylamine, diisopropylamine, and more preferably sodium hydroxide or potassium hydroxide.

[0160] In one embodiment, the compound M1 prepared according to the above step F has a purity of up to 99.85% and a yield of up to 97.2%.

[0161] In some specific embodiments of the present invention, the hydrochloride of roxatidine acetate comprises the following steps: adding hydrogen chloride to the isopropyl acetate solution of roxatidine acetate, precipitating roxatidine acetate hydrochloride, collecting the material, and obtaining. During the process investigation of the hydrochloride of roxatidine acetate, the inventor unexpectedly found that the hydrochloride of roxatidine acetate obtained by using isopropyl acetate as a solvent has better properties, can produce white crystalline particles, large particle size, easy to filter, easy to dry, and the use of isopropyl acetate as a salt-forming solvent can achieve a beneficial effect significantly better than other solvents.

[0162] In summary, in order to solve the problems of long reaction time, high reaction temperature, complicated operation, low yield, low purity of raw materials, etc. in some steps of the current synthesis process, the present invention innovates and optimizes the synthesis route, and the most suitable synthesis route for industrialization is determined as follows:

[0163]

[0164] Specifically, the method comprises the following steps: firstly, m-hydroxybenzaldehyde is reacted with piperidine to obtain a high-purity compound M1 (3-(1-piperidinylmethyl)phenol), the compound M1 is reacted with 3-chloropropylamine hydrochloride to obtain an intermediate M2 (3-(3-piperidin-1-ylmethylphenoxy)propylamine), the intermediate M2 is reacted with acetoxyacetyl chloride to obtain an intermediate M3 (crude roxatidine acetate), and the intermediate M3 is hydrolyzed to obtain an intermediate M4 (crude roxatidine). The intermediate M4 is salified with oxalic acid and then recrystallized to obtain a high-purity intermediate M5 (roxatidine hemioxalate), the intermediate M5 is desalted to obtain an intermediate M6 (refined roxatidine), the intermediate M6 is reacted with acetic anhydride to obtain an intermediate M7 (refined roxatidine acetate), the intermediate M7 is salified with hydrogen chloride to obtain an intermediate M8 (crude roxatidine acetate hydrochloride), and the intermediate M8 is refined to obtain high-purity roxatidine acetate hydrochloride.

[0165] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0166] Example 1 Preparation of Roxatidine Hydrochloride Acetate

[0167] 1. Preparation of Intermediate 1 (3-(1-piperidinylmethyl)phenol, M1)

[0168] In a 100L glass kettle, add 5.0 times 50.00kg of anhydrous formic acid and 1.0 times 10.00kg of m-hydroxybenzaldehyde in sequence. After the addition, stir and heat to 120℃~140℃, add 2.43 times 24.30kg of piperidine dropwise, control the reaction temperature at 120℃~140℃, and keep the reaction warm for 1.5 hours after the addition.

[0169] After the reaction is complete, the reaction liquid is cooled to 20°C to 30°C, 5.0 times 50.00 kg of purified water is added, and the mixture is transferred to a 300-liter reactor. A 40% aqueous sodium hydroxide solution is slowly added to adjust the pH to 8.5±0.5, 0.10 kg of 1% seed crystals are added, and the pH is continued to be adjusted until solids are obviously precipitated from the reaction liquid. The mixture is stirred for 30 to 60 minutes to grow crystals, and the pH is continued to be adjusted to 10.5±0.5. The mixture is stirred at 25±5°C for 1 to 2 hours to crystallize, and filtered. The filter cake is washed three times with 2.0 times 20.00 kg of water, and the obtained solid is vacuum dried at 40±5°C for 4 hours to obtain 15.19 kg of intermediate 1, with a yield of 97.2% (based on m-hydroxybenzaldehyde). ESI-MS m / z: 192.2 [M +H]+; 1 H-NMR (400MHz, DMSO-d6) δ: 1.34-1.42 (m, 2H), 1.45-1.51 (m, 4H), 2.28 (s, 4H), 3.31 (s, 2H), 6.60-6.63 (m, 1H), 6.63-6.74 (m, 2H), 7.07 (t, J = 7.7 Hz, 1H), 9.44 (s, 1H); 13C-NMR (100MHz, DMSO-d6) δ: 24.52, 26.06, 54.41, 63.43, 114.18, 115.93, 119.63, 129.36, 140.59, 157.82; HPLC purity: 99.85% (HPLC spectrum see Figure 1 ); Melting point: 137.2~138.8℃.

[0170] 2. Preparation of Intermediate 2 (3-(3-piperidin-1-ylmethylphenoxy)propylamine, M2)

[0171] Preparation of 3-chloropropylamine hydrochloride solution: Turn on stirring, add 45.00 kg of 3.0 times N,N-dimethylformamide and 12.15 kg of 0.81 times 3-chloropropylamine hydrochloride to a 50-liter reactor, stir and dissolve at 30±5℃ for later use.

[0172] Start stirring, add 30.00 kg of 3.0 times N,N-dimethylformamide and 15.00 kg of 1.0 times intermediate 1 to the 100L reactor in sequence, add 21.75 kg of 1.45 times sodium hydroxide under stirring, and after the addition is complete, stir and heat to 65±5°C.

[0173] When the internal temperature rises to 65±5°C, add the pre-prepared 3-chloropropylamine hydrochloride solution dropwise, and react at a temperature of 60-75°C. After the addition is completed, keep the temperature at 65±5°C and react for 1.5 hours. The internal temperature was cooled to 20±5°C, 30.00 kg of 2.0 times dichloromethane was added for dilution, the mixture was placed in a transfer barrel, filtered, and the filter cake was slowly rinsed with 75.00 kg of 5.0 times dichloromethane. After the filter cake was cleaned, the filtrate was transferred to a 300L reactor, 90.00 kg of 6.0 times purified water was added, stirred for 5-10 min, and allowed to stand for separation. The aqueous layer was extracted with 45.00 kg of 3.0 times dichloromethane, and the organic phases obtained twice were combined and washed with 60.00 kg of 4.0 times purified water for 4 times. 30.00 kg of 2.0 times anhydrous sodium sulfate was added to the organic phase, stirred and dried for 2.5±0.5 hours, filtered, and the filter cake was slowly rinsed with 30.00 kg of 2.0 times dichloromethane for 2 times to obtain a dichloromethane solution of M2. ESI-MS m / z: 249.2[M+H]+; 1H-NMR (400MHz, DMSO-d6) δ: 1.38 (q, J=6.2Hz, J=6.8Hz, 2H), 1.45-1.51 (m, 4H), 1.74-1.80 (m, 2H), 2.30 (d, J=5.9Hz, 4H), 2.69 (t, J=6.7Hz, 2H), 3.36 (s, 2H), 3.99 (t, J=6.4Hz, 2H), 6.74-6.86 (m, 3H), 7.19 (t, J=8.0Hz, 1H); 13C-NMR (100MHz, DMSO-d6) δ: 24.50, 26.05, 33.22, 38.88, 54.38, 63.30, 65.80, 113.08, 115.09, 121.19, 129.48, 140.77, 159.13.

[0174] 3. Preparation of intermediate 3 (crude roxatidine acetate, M3)

[0175] The feeding amount in this step is measured based on M1.

[0176] The filtrate was transferred to a 300L reactor, stirring was started, 10.20kg of 0.68 times triethylamine was added, and under nitrogen protection, the internal temperature was lowered to 15±5°C, and 12.90kg of 0.86 times acetoxyacetyl chloride was added dropwise at an internal temperature of 15±5°C. After the addition was completed, the internal temperature was kept at 15±5°C and stirred for 1 hour. The reaction liquid was filtered, and the filter cake was slowly washed with 30.00kg of 2.0 times dichloromethane. The filtrate was concentrated using a 200L reactor until no obvious fraction was distilled out, and 30.00kg of 2.0 times ethanol was added to obtain M3 solution.

[0177] 4. Preparation of intermediate 4 (roxatidine crude product, M4)

[0178] The feeding amount in this step is measured based on M1.

[0179] Preparation of 30% sodium hydroxide aqueous solution: Add 8.70 kg of 0.58 times purified water into the transfer barrel, add 3.75 kg of 0.25 times sodium hydroxide while stirring, stir and dissolve completely to prepare a 30% sodium hydroxide aqueous solution, cool to room temperature and set aside.

[0180] Preparation of sodium chloride aqueous solution: add 60.00 kg of 4.0 times water and 15.00 kg of 1.0 times sodium chloride into a 200-liter reactor and stir to obtain the solution.

[0181] The M3 solution was transferred to a 200-liter reactor, stirred, cooled, and the prepared 30% sodium hydroxide aqueous solution was added dropwise at an internal temperature of 35±5°C. After addition, the internal temperature was controlled at 35±5°C for 0.5 hours. 2.0 times water (30.00 kg) and 3.0 times isopropyl acetate (45.00 kg) were added under stirring, stirred for 5 to 10 minutes, and allowed to stand for separation. The aqueous layer was extracted with 3.0 times isopropyl acetate (45.00 kg), the organic layers were combined, and the organic layers were washed with 5.0 times brine (75.00 kg) for 4 times. The organic phase was concentrated under reduced pressure at an external temperature of 45±5°C until no obvious fractions were found, and crude roxatidine (M4) was obtained.

[0182] 5. Preparation of intermediate 5 (roxatidine oxalate, M5)

[0183] Add 75.00 kg of 5.0 times anhydrous ethanol to the residue M4, heat to dissolve, transfer to a 300-liter reactor, raise the internal temperature to 80±5°C under stirring, add about 25.94 kg of 51% oxalic acid ethanol solution, add 0.15 kg of 1% oxalate seed crystals, and after addition, keep warm and stir for 30 to 45 minutes, continue to cool to 20±5°C for crystallization for 2.0 hours, filter, and rinse the filter cake with 30.00 kg of 2.0 times anhydrous ethanol to obtain a crude wet product of roxatidine oxalate, weighing 21.66 kg. The wet product is tested with fast water to dry the wet weight of 7.8%, which is converted to a dry weight of 19.97 kg. The yield is 71.9% (based on M1).

[0184] Stirring was started, 119.40 kg of 6.0 times 85% w / w ethanol and 1.0 times roxatidine oxalate crude wet product (19.90 kg in dry form) were added to the 300L reactor in sequence, external circulation was started, the temperature was raised to 80±5°C with stirring, and the mixture was kept warm and stirred for 2.0 to 2.5 hours, the temperature was lowered to 60±5°C, 0.20 kg of 1% seed was added, the mixture was kept warm and stirred for 30 to 60 minutes, the temperature was further lowered to an internal temperature of 20±5°C for crystallization for 2.0 hours, filtered, and the filter cake was slowly rinsed with 59.7 kg of 3.0 times anhydrous ethanol to obtain roxatidine oxalate refined wet product, which was vacuum dried at 40±5°C for 4 hours, weighing 17.89 kg, with a yield of 89.6% (based on the crude product). ESI-MS m / z: 307.2[M+H]+; 1H-NMR (400MHz, DMSO-d6) δ: 1.44 (s, 2H), 1.60 (s, 4H), 1.85-1.92 (m, 2H), 2.67 (s, 4H), 3.27 (q, J=6.6Hz, 2H), 3.79 (s, 4H), 3.98 (t, J=6.2Hz, 2H), 6.88-6.96 (m, 3H), 7.27 (d, J=7.8Hz, 1H), 7.85 (s, 1H); 13C-NMR (400MHz, DMSO-d6) δ: 23.19, 24.39, 29.44, 35.83, 53.29, 61.35, 61.94, 65.98, 114.51, 116.32, 122.52, 129.93, 159.07, 165.13, 172.26; HPLC purity: 99.94% (HPLC spectrum see Figure 2 ); Melting point: 171.2~172.4℃.

[0185] 6. Preparation of intermediate 6 (refined roxatidine, M6)

[0186] Preparation of potassium hydroxide solution: Add 8.01 kg of 0.45 times purified water into a plastic bucket, add 4.45 kg of 0.25 times potassium hydroxide dropwise while stirring, stir until completely dissolved and set aside.

[0187] Add 89.00 kg of 5.0 times purified water and 17.80 kg of 1.0 times roxatidine oxalate to a 300L reactor, stir and cool to 15±5°C, add the prepared potassium hydroxide aqueous solution dropwise while stirring, control the temperature to 15±5°C, after adding, keep warm and stir for 20 to 30 minutes, add 53.40 kg of 3.00 times isopropyl acetate, stir for 5 to 10 minutes, stand and separate, use 35.60 kg of 2.00 times isopropyl acetate for the aqueous phase Extract once more, stir for 5 to 10 minutes, stand for separation, combine the organic layers, rinse the reactor wall with purified water, wash the organic layer with 106.80 kg of 6.0 times purified water for 4 times, stir for 5 to 10 minutes each time, stand for separation, concentrate the organic layer at an external temperature of 45 ± 5 ° C to a vacuum degree of <-0.085 MPa, and continue to concentrate for 1 to 2 hours after there is no obvious distillate, take a sample of about 2 g to detect the moisture content, the moisture content is <4%, stop concentrating, add 71.2 kg of 4.0 times isopropyl acetate to dissolve the oil, filter, wash the dissolution tank and the filter with 17.80 kg of 1.0 times isopropyl acetate, combine the organic layers to obtain a refined solution of roxatidine.

[0188] 7. Preparation of intermediate 7 (refined roxatidine acetate, M7)

[0189] The feeding amount in this step is measured based on M5.

[0190] Start stirring the roxatidine refined product solution in the 300L reactor, add 18.16kg of 1.02 times acetic anhydride under stirring, react at 45±5℃ with stirring for 2.0 hours, cool to room temperature, add 35.60kg of 2.0 times isopropyl acetate and 12.10kg of 0.68 times isopropanol and stir for 30 to 60 minutes to obtain M7 isopropyl acetate mixed solution.

[0191] 8. Preparation of intermediate 8 (crude roxatidine acetate hydrochloride, M8)

[0192] The feeding amount in this step is measured based on M5.

[0193] M7 isopropyl acetate mixed solution, temperature controlled at 15±5°C, 4.45kg of 0.25 times of hydrogen chloride isopropyl acetate solution with a content of about 4.15% was slowly added dropwise under stirring, after the dropwise addition, 0.18kg of 1% seed was added, the mixture was kept warm and stirred for 10 to 20 minutes, and 44.5kg of about 2.50 times of hydrogen chloride isopropyl acetate solution with a content of about 4.15% was continued to be added dropwise. After the dropwise addition, the mixture was stirred for crystallization for 1.0 to 1.5 hours, filtered, and the filter cake was washed 4 times with 53.40kg of 3.0 times of isopropyl acetate to obtain a crude wet product of roxatidine acetate hydrochloride. The wet product was dried at 40±5°C for 8 hours, and the material was obtained to obtain M8, weighing 17.54kg, with a yield of 89.7% (based on M5).

[0194] 9. Preparation of Refined Roxatidine Acetate Hydrochloride

[0195] Add 105.00 kg of 6.0 times N, N-dimethylformamide and 17.50 kg of 1.0 times crude roxatidine acetate hydrochloride to a 200-liter reactor, heat to 55±5°C while stirring, stir and dissolve, filter to the clean area, wash the pipeline with 1.0 times N, N-dimethylformamide preheated to 55±5°C, cool to 35±5°C, add 8.75 kg of 0.5 isopropyl acetate dropwise, add 0.18 kg of 0.01 times seed crystals, and stir for 30 to 60 minutes. The reaction mixture was stirred for 2 hours at 5 ± 5 ° C., and the reaction mixture was centrifuged. The reaction mixture was washed with 52.50 kg of 3.0 times isopropyl acetate to obtain a wet product of roxatidine acetate hydrochloride. The wet product was dried at 40 ± 5 ° C. for 8 hours. The refined product of roxatidine acetate hydrochloride was obtained, weighing 15.96 kg, with a yield of 91.2% (based on M8). ESI-MS m / z: 349.2[M+H] +; 1H-NMR (400MHz, DMSO-d6) δ: 1.29-1.39 (m, 1H), 1.66-1.78 (m, 1H), 1.80-1.84 (m, 4H), 1.86-1.92 (m, 2H), 2.08 (s, 3H), 2.76-2.86 (m, 2H), 3.22-3.27 (m, 4H), 4.01 (t, J=6.0Hz, 2H), 4.19 (d, J=5.2Hz, 2H), 4.43 (s, 2H), 6.99 (dd, J=8.4Hz, J=2.0Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 7.27 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 8.15 (t, J = 5.2 Hz, 1H), 10.61 (bs, 1H); 13C-NMR (100 MHz, DMSO-d6) δ: 21.06, 21.94, 22.47, 29.21, 35.87, 51.99, 59.20, 62.73, 65.75, 115.93, 117.80, 123.87, 130.21, 131.73, 159.06, 167.22, 170.40. Melting point: 148.0-149.5°C; HPLC purity: 99.95% (single impurity <0.05%). The HPLC spectrum of the final product roxatidine acetate hydrochloride is shown in Figure 3 , TGA-DSC spectrum see Figure 4 , XRD spectrum see Figure 5 .

[0196] Example 2 Preparation of 3-(1-piperidinylmethyl)phenol (Compound M1)

[0197] To the reaction flask, add 5.0 times 50.0g of anhydrous formic acid and 1.0 times 10.0g of m-hydroxybenzaldehyde in sequence. After the addition, stir and heat to 110°C ~ 115°C, add 3.5 times 35.0g of piperidine dropwise, control the reaction temperature at 110°C ~ 115°C, keep the reaction warm for 1.5 hours after the addition, follow the TLC, the reaction is not complete, react for 6 hours, and a small amount of it is not completely reacted. The reaction solution was cooled to 20°C to 30°C, 5.0 times 50.0 g of purified water was added, and 40% sodium hydroxide aqueous solution was slowly added to adjust the pH to 8.5±0.5. The pH was continued to be adjusted until solids were obviously precipitated from the reaction solution, and the mixture was stirred for 30 to 60 minutes to grow crystals. The pH was continued to be adjusted to 10.5±0.5, and the mixture was stirred at 25±5°C for crystallization for 1 to 2 hours. The filter cake was washed three times with 2.0 times 20.0 g of water, and the obtained solid was vacuum dried at 40±5°C for 4 h to obtain 12.6 g of compound M1 with a yield of 81% (based on m-hydroxybenzaldehyde) and HPLC purity of 98.5%.

[0198] Example 3 Refining of crude roxatidine acetate hydrochloride

[0199] Add 6.0 times N, N-dimethylformamide 105.0g and 1.0 times roxatidine acetate crude product 17.5g (take M8 prepared according to Example 1) to the reaction bottle, heat to 55±5°C under stirring, stir and dissolve, filter, wash with 1.0 times N, N-dimethylformamide preheated to 55±5°C, cool to 35±5°C, add 0.5 isopropyl acetate 8.7g dropwise, add 0.01 times seed 0.2g, stir for 30-60 The mixture was stirred for 2 hours at 15 to 20 ° C., and the mixture was centrifuged and washed with 52.5 g of 3.0 times isopropyl acetate to obtain a wet product of roxatidine acetate hydrochloride. The wet product was dried at 40 ± 5 ° C. for 8 hours. The refined product of roxatidine acetate hydrochloride was obtained, weighing 13.6 g, with a yield of 78% (based on the mass of the crude product of roxatidine acetate hydrochloride), and HPLC purity: 99.95% (single impurity <0.05%).

[0200] Comparative Example Refining of Crude Roxatidine Acetate Hydrochloride

[0201] The crude product of roxatidine acetate hydrochloride was recrystallized according to the roxatidine acetate hydrochloride refining process of reference route 1, and the crude product was M8 prepared according to Example 1.

[0202] Under mechanical stirring, add 30.0 g of crude roxatidine acetate hydrochloride and 150 mL of ethanol to a three-necked flask, heat to 60°C to dissolve, add 5.0 g of activated carbon and reflux for 30 min, filter while hot, cool the filtrate to 10°C, slowly add 450 mL of ethyl acetate, precipitate a white solid, and continue stirring for 4 h. Filter by suction and dry under reduced pressure to obtain 23.2 g of the product, with a yield of 77.3%, a purity of 98.9%, and a roxatidine content of 1.1%. See HPLC spectrum Figure 6 .

[0203] It should be noted that the specific features, structures, materials or characteristics described in this specification may be combined in any one or more embodiments in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments and features of the different embodiments described in this specification without contradiction.

Claims

1. A method for refining roxatidine acetate hydrochloride, characterized in that: Recrystallization is performed using N,N-dimethylformamide as a good solvent and isopropyl acetate as a poor solvent; comprising the following steps: a. Adding a good solvent: Mix crude roxatidine acetate hydrochloride and N,N-dimethylformamide, and heat to dissolve, wherein the mass ratio of crude roxatidine acetate hydrochloride to N,N-dimethylformamide is 1:(4-10); b. Adding a poor solvent: adding isopropyl acetate to the solution obtained in step a, cooling to 0-10° C. to precipitate roxatidine acetate hydrochloride, collecting the material, and obtaining a refined roxatidine acetate hydrochloride, wherein the mass ratio of crude roxatidine acetate hydrochloride to isopropyl acetate is 1:(4-10); Wherein, step a is heated to 50-80°C to dissolve; Step a: heating and dissolving, followed by hot filtration; Step b: adding isopropyl acetate in batches: first cool to 30-40° C., add 0.4-0.6 times the mass of the crude roxatidine acetate hydrochloride, add seed crystals, stir evenly, and then continue to add the remaining isopropyl acetate, cool to 0-10° C. to precipitate roxatidine acetate hydrochloride.

2. The purification method according to claim 1, characterized in that: The mass ratio of crude roxatidine acetate hydrochloride:N,N-dimethylformamide is 1:

6.

3. The purification method according to claim 1, characterized in that: The mass ratio of crude roxatidine acetate hydrochloride: isopropyl acetate is 1:

6.

4. The purification method according to claim 1, characterized in that: Step a: heat to 50-60°C to dissolve.

5. The purification method according to claim 1, characterized in that: Based on the mass of the crude product of roxatidine acetate hydrochloride, 0.05-5% of seed crystals are added.

6. The purification method according to claim 1, characterized in that: Based on the mass of the crude product of roxatidine acetate hydrochloride, 0.1-2% of seed crystals are added.

7. The purification method according to claim 1, characterized in that: Based on the mass of the crude product of roxatidine acetate hydrochloride, 0.5-1.5% of seed crystals are added.

8. The purification method according to claim 1, characterized in that: The mixture was stirred at 0-10°C for more than 1 hour to crystallize.

9. The purification method according to claim 1, characterized in that: The crystallization was stirred at 0-10°C for 1.5-2.5 hours.

10. The preparation method of roxatidine acetate hydrochloride is characterized in that: The steps include: Roxatidine is obtained by the following preparation method: Step A: Compound M1, 3-chloropropylamine or its salt and a base are reacted in N,N-dimethylformamide to obtain intermediate M2: Step B: Intermediate M2 reacts with acetoxyacetyl chloride to obtain intermediate M3: Step C: hydrolyze the intermediate M3 to obtain the crude roxatidine M4: Step D: The crude roxatidine M4 is salified with oxalic acid to obtain the intermediate M5: Step E: The intermediate M5 reacts with a base to obtain the refined roxatidine M6: Roxatidine acetate is obtained according to the following preparation method: roxatidine and acetic anhydride are used as raw materials, isopropyl acetate is added as a reaction solvent, and reacts at 10 to 50° C. to generate roxatidine acetate; wherein, based on the mass of roxatidine hemioxalate, the mass ratio of roxatidine hemioxalate to acetic anhydride is 3.5: (1.0～6.2)； Then, roxatidine acetate is converted into hydrochloride, and finally, the refined roxatidine acetate hydrochloride is obtained according to the refining method according to any one of claims 1 to 9.

11. The preparation method according to claim 10, characterized in that: The step of preparing roxatidine acetate satisfies at least one of the following: React at 40-50°C; Based on the mass of roxatidine hemioxalate, the mass ratio of roxatidine hemioxalate to acetic anhydride is 3.5:(4.0-4.6); Reaction time 1.5 to 2.5 hours; Based on the mass of roxatidine hemioxalate, add 4 to 5 times the reaction solvent isopropyl acetate; The post-reaction treatment is to add an acetic anhydride quenching solvent or a mixed solvent of an acetic anhydride quenching solvent and isopropyl acetate, and stir evenly; wherein the acetic anhydride quenching solvent is selected from lower alcohols.

12. The preparation method according to claim 11, characterized in that: Reaction time: 2.0 hours.

13. The preparation method according to claim 11, characterized in that: The acetic anhydride quenching solvent is selected from at least one of methanol, ethanol, isopropanol and n-propanol.

14. The preparation method according to claim 10, characterized in that: The steps of preparing roxatidine satisfy at least one of the following: The reaction temperature of step A is 30-70°C; The reaction time of step A is 1.2 to 1.8 hours; After the reaction in step A is completed, the reaction solution is extracted with an organic solvent to obtain a solution of intermediate M2, which is then transferred to step B without purification; Adding an acid binding agent to the reaction system of step B; The reaction solvent of step B is dichloromethane; The reaction temperature of step B is -10 to 45°C; After the reaction in step B is completed, the reaction solution is subjected to solid-liquid separation, the liquid phase is collected and concentrated to obtain intermediate M3, which is then transferred to step C without purification; Step C is subjected to alkaline hydrolysis; The reaction solvent of step C is ethanol or a mixed solvent of ethanol and water; The reaction temperature of step C is -10 to 45°C; After the reaction in step C is completed, the reaction solution is extracted with an organic solvent and concentrated to obtain a crude roxatidine product M4, which is then transferred to step D without purification; The reaction solvent in step D is selected from at least one of methanol, ethanol and isopropanol; The reaction temperature of step D is 20 to 90°C; After the reaction in step D is completed, the temperature is lowered to 15-25°C for crystallization; Step D comprises recrystallizing the intermediate M5, wherein the recrystallization solvent is a mixed solvent of at least one of methanol, ethanol, and isopropanol and water; Based on the mass of compound M1, 0.05% to 5% seed crystals are added during the recrystallization process in step D; The base described in step E is potassium hydroxide; The reaction solvent of step E is water; The reaction temperature of step E is -10 to 45°C; After the reaction in step E is completed, the reaction solution is extracted with an organic solvent and concentrated to obtain roxatidine refined product M6; The moisture content of the refined roxatidine M6 is controlled to be less than 6%.

15. The preparation method according to claim 10, characterized in that: Compound M1 is prepared by the following steps F: m-Hydroxybenzaldehyde and piperidine react in formic acid to prepare compound M1.

16. The preparation method according to claim 15, characterized in that: At least one of the following is met: In step F, the mass ratio of hydroxybenzaldehyde to piperidine is 1:(1.5-5.0); In step F, the mass ratio of hydroxybenzaldehyde to formic acid is 1:(1.0-10.0); The reaction temperature of step F is 80-140°C; The reaction time of step F is 1.2 to 1.8 hours; The post-reaction treatment in step F is to adjust the pH to 8.0-12.0 to precipitate compound M1.

17. The preparation method according to claim 10, characterized in that: The method for converting roxatidine acetate into hydrochloride comprises the following steps: adding hydrogen chloride to an isopropyl acetate solution of roxatidine acetate to precipitate roxatidine acetate hydrochloride, and collecting the material to obtain the product.

18. The preparation method according to claim 17, characterized in that: The step of converting roxatidine acetate into hydrochloride satisfies at least one of the following: Add hydrogen chloride at 0-45°C; Hydrogen chloride is added in the form of a solution of hydrogen chloride in isopropyl acetate; After the addition of hydrogen chloride is complete, the mixture is stirred and crystallized for 1.0 to 1.5 hours.

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