A method for preparing lafutidine

Abstract

This invention belongs to the field of medicinal chemistry and relates to a method for preparing lafutidine. The method involves an aminolysis reaction of the compound shown in Formula 2 with a primary amine compound in an organic solvent, followed by the addition of a base to the resulting reaction solution for further deprotection. The resulting compound, shown in Formula 4, undergoes a condensation reaction with the compound shown in Formula 5 to obtain lafutidine. Compared with existing technologies, the lafutidine preparation method provided by this invention has advantages such as low production cost, good safety, high purity, and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a method for preparing lafutidine. Background Technology

[0002] Lafutidine, chemically named (±)-2-[2-(furanmethyl)sulfinyl]-N-[4-[4-(piperidinylmethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetamide, has the following chemical structure:

[0003]

[0004] Lafutidine is a new generation of long-acting, potent H2-receptor antagonists, primarily used to treat duodenal ulcers, gastric ulcers, gastroesophageal reflux disease, and peptic ulcers. Compared to previous generation H2 receptor antagonists, such as ranitidine and famotidine, lafutidine has a lower recurrence rate after ulcer healing, requires a smaller dosage, has higher safety profile, and is better tolerable.

[0005]

[0006] Currently, the synthetic route shown above is commonly used to prepare lafutidine raw material in existing technologies. Specifically, the maleate of compound 2 is used as the starting material, and compound 4 is generated under the action of an aminolysis reagent. Compound 4 is then condensed with compound 5 to obtain lafutidine (as shown in formula 1). However, there are certain problems in the preparation of compound 4. For example, hydrazine hydrate is often used as a raw material in existing technologies to carry out an aminolysis reaction on compound 2. However, hydrazine hydrate is unstable, highly toxic, volatile and explosive, and its use poses safety hazards. In addition, crude lafutidine contains dihydrolafutidine impurities, which are difficult to remove. Chinese patent CN102212060A discloses the use of methylamine or ethylamine as amination reagent to synthesize compound 4 by amination of compound 2. However, methylamine and ethylamine are gaseous at room temperature and pressure. Even their aqueous solutions are highly volatile and can easily evaporate into the atmosphere. Gaseous methylamine mixed with air can form an explosive mixture, which can cause combustion and explosion when exposed to open flames or high heat. In addition, the hydrolysis process of methylamine and ethylamine will result in a solid-liquid mixture, which makes the reaction process very slow, usually more than 10 hours, thus reducing the reaction efficiency. Chinese patent CN110642832A discloses the use of ethylenediamine as an aminolysis reagent to aminolyze compound 2. However, when ethylenediamine comes into contact with open flames, high heat, or oxidizers, it poses a risk of combustion and explosion, resulting in safety hazards. Furthermore, when using hydroxylamine hydrochloride to aminolyze compound 2, hydroxylamine hydrochloride is highly toxic, and production equipment should be sealed to prevent leaks and spills. Operators should wear protective equipment to ensure life and environmental safety. Further, this patent discloses the use of ethanolamine as an aminolysis reagent to aminolyze compound 2. However, ethanolamine is a high-boiling-point solvent with a boiling point as high as 170°C, and post-processing inevitably leaves residues in the API, causing solvent residues or related impurities. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing lafutidine that addresses the shortcomings of the prior art. This method has low reaction cost, good safety, high purity, and is suitable for large-scale industrial production.

[0008] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0009] This invention discloses a method for preparing the compound shown in Formula 4, comprising the following steps:

[0010] (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained.

[0011] ;

[0012] R is selected from n-butyl or n-propyl.

[0013] In some embodiments, to shorten the reaction time and ensure the reaction yield and product purity, so as to be more suitable for industrial scale-up production, R is preferably n-butyl.

[0014] In some embodiments, in step (1), the organic solvent is an alcohol solvent; preferably, the alcohol solvent is any one or a combination of methanol, ethanol and isopropanol; more preferably, the alcohol solvent is any one or a combination of methanol and ethanol; to further improve the reaction yield and shorten the reaction time, the alcohol solvent is preferably methanol.

[0015] In some embodiments, in step (1), there are no special requirements for the amount of solvent used; it is sufficient to dissolve and / or disperse the raw materials evenly. Preferably, the mass-volume ratio of the compound of formula 2 to the solvent is 1 g: (5~20) mL, and more preferably 1 g: (7~10) mL.

[0016] In some embodiments, in step (1), the alkaline substance is any one or a combination of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the alkaline substance is sodium hydroxide; more preferably, the alkaline substance is fed in the form of an aqueous solution, and further preferably, the mass concentration of the alkaline substance in the aqueous solution is 1%~20%, preferably 3%~10%; the molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:1~20, preferably 1:2~8.

[0017] In some embodiments, in step (1), preferably, the molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:5.

[0018] In some embodiments, in step (1), the molar ratio of the compound shown in Formula 2 to the primary amine compound is 1:10~30, preferably 1:18~22, and more preferably 1:20.

[0019] In some embodiments, in step (1), the aminolysis reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C; the deprotection reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C.

[0020] In some embodiments, in step (1), the aminolysis reaction takes 4 h to 24 h, preferably 4 h to 8 h.

[0021] In some embodiments, in step (1), the deprotection reaction takes 1 to 3 hours, preferably 2 hours.

[0022] In some embodiments, after the deprotection reaction in step (1) is completed, the organic solvent is removed by concentration, and the compound shown in Formula 4 in the reaction solution is extracted with an extraction solvent. The organic phase is retained and the organic phase is washed to obtain a reaction solution containing the compound shown in Formula 4.

[0023] The extraction solvent is any one or a combination of several of aromatic solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents; preferably, the extraction solvent is an ester solvent; more preferably, the ester solvent is any one or a combination of several of methyl acetate, ethyl acetate and isopropyl acetate, and even more preferably isopropyl acetate;

[0024] The amount of the extraction solvent, based on the compound shown in Formula 2, is 1 g: (5~30) mL, preferably 1 g: (15~25) mL, and more preferably 1 g: 20 mL.

[0025] The washing organic phase is selected from those washed sequentially with an alkaline substance solution and a sodium chloride solution; further, the mass concentration of the alkaline substance in the alkaline substance solution is 1%~20%, and the mass concentration of sodium chloride in the sodium chloride solution is 1%~20%.

[0026] In some embodiments, in step (1), the washing of the organic phase is preferably performed by sequentially washing with an alkaline solution and a sodium chloride solution, which can effectively remove the impurities generated in the reaction of step (1), so that the impurities generated when the reaction solution of compound 4 participates in the subsequent reaction to prepare lafutidine are lower and the product purity is higher; the alkaline solution is water as the solvent and any one or a combination of two of sodium hydroxide and potassium hydroxide as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 15%; the sodium chloride solution is water as the solvent and sodium chloride as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 20%.

[0027] Furthermore, this invention discloses a method for preparing lafutidine, comprising the following steps:

[0028] (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained.

[0029] ;

[0030] (2) The compound of formula 4 obtained in step (1) undergoes a condensation reaction with the compound of formula 5 to obtain lafutidine of formula 1.

[0031] ;

[0032] R is selected from n-butyl or n-propyl.

[0033] In some embodiments, to shorten the reaction time and ensure the reaction yield and product purity, so as to be more suitable for industrial scale-up production, R is preferably n-butyl.

[0034] In some embodiments, in step (1), the organic solvent is an alcohol solvent; preferably, the alcohol solvent is any one or a combination of methanol, ethanol and isopropanol; more preferably, the alcohol solvent is any one or a combination of methanol and ethanol; to further improve the reaction yield and shorten the reaction time, the alcohol solvent is preferably methanol.

[0035] In some embodiments, in step (1), there are no special requirements for the amount of solvent used; it is sufficient to dissolve and / or disperse the raw materials evenly. Preferably, the mass-volume ratio of the compound of formula 2 to the solvent is 1 g: (5~20) mL, and more preferably 1 g: (7~10) mL.

[0036] In some embodiments, in step (1), the alkaline substance is any one or a combination of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the alkaline substance is sodium hydroxide; more preferably, the alkaline substance is fed in the form of an aqueous solution, and further preferably, the mass concentration of the alkaline substance in the aqueous solution is 1%~20%, preferably 3%~10%; the molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:1~20, preferably 1:2~8.

[0037] In some embodiments, in step (1), preferably, the molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:5.

[0038] In some embodiments, in step (1), the molar ratio of the compound shown in Formula 2 to the primary amine compound is 1:10~30, preferably 1:18~22, and more preferably 1:20.

[0039] In some embodiments, in step (1), the aminolysis reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C; the deprotection reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C.

[0040] In some embodiments, in step (1), the aminolysis reaction takes 4 h to 24 h, preferably 4 h to 8 h.

[0041] In some embodiments, in step (1), the deprotection reaction takes 1 to 3 hours, preferably 2 hours.

[0042] In some embodiments, after the deprotection reaction in step (1) is completed, the organic solvent is removed by concentration, and the compound shown in Formula 4 in the reaction solution is extracted with an extraction solvent. The organic phase is retained and the organic phase is washed to obtain a reaction solution containing the compound shown in Formula 4.

[0043] The extraction solvent is any one or a combination of several of aromatic solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents; preferably, the extraction solvent is an ester solvent; more preferably, the ester solvent is any one or a combination of several of methyl acetate, ethyl acetate and isopropyl acetate, and even more preferably isopropyl acetate;

[0044] The amount of the extraction solvent, based on the compound shown in Formula 2, is 1 g: (5~30) mL, preferably 1 g: (15~25) mL, and more preferably 1 g: 20 mL.

[0045] The washing organic phase is selected from those washed sequentially with an alkaline substance solution and a sodium chloride solution; further, the mass concentration of the alkaline substance in the alkaline substance solution is 1%~20%, and the mass concentration of sodium chloride in the sodium chloride solution is 1%~20%.

[0046] In some embodiments, in step (1), the washing of the organic phase is preferably performed by sequentially washing with an alkaline solution and a sodium chloride solution, which can effectively remove the impurities generated in the reaction of step (1), so that the impurities generated when the reaction solution of compound 4 participates in the subsequent reaction to prepare lafutidine are lower and the product purity is higher; the alkaline solution is water as the solvent and any one or a combination of two of sodium hydroxide and potassium hydroxide as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 15%; the sodium chloride solution is water as the solvent and sodium chloride as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 20%.

[0047] In some embodiments, in step (2), the ratio of the amount of compound shown in Formula 5 to the amount of compound shown in Formula 4 is calculated based on the amount of compound shown in Formula 2 used during its preparation. The molar ratio of compound shown in Formula 5 to compound shown in Formula 2 is 0.8~1.2:1.0, preferably 0.9~1.1:1.0, and more preferably 1.0:1.0.

[0048] In some embodiments, in step (2), the condensation reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C.

[0049] In some embodiments, in step (2), the condensation reaction takes 1 to 4 hours, preferably 2 hours.

[0050] In step (2), since the reaction solution containing the compound shown in Formula 4 obtained in step (1) contains an extraction solvent, no solvent may be added in the condensation reaction; alternatively, other solvents may be added, such as organic solvents, for example, any one or a combination of aromatic solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents. Preferably, the extraction solvent is an ester solvent, more preferably, the ester solvent is any one or a combination of methyl acetate, ethyl acetate and isopropyl acetate, and even more preferably, isopropyl acetate.

[0051] In some embodiments, in step (2), after the condensation reaction is completed, the reaction solution is filtered and washed with alkaline solution and water in sequence, and the organic phase is retained; an antisolvent is added to the organic phase for cooling and crystallization, and a solid is precipitated. Solid-liquid separation is performed to obtain lafuratedin as shown in Formula 1.

[0052] The antisolvent is any one or a combination of several of methyl tert-butyl ether, n-heptane, n-hexane and isopropyl ether, preferably methyl tert-butyl ether; preferably, the organic phase is concentrated before adding the antisolvent to the organic phase, and the volume ratio of the concentrated organic phase to the antisolvent is 1:1 to 4, preferably 1:2.

[0053] In some embodiments, in step (2), the alkaline solution is water as the solvent and sodium hydroxide and potassium hydroxide as the solute, and the mass percentage concentration of the solute in the solution is 1% to 20%, preferably 5% to 15%.

[0054] In some embodiments, in step (2), after the condensation reaction is completed, the reaction solution is washed with alkaline solution and water in sequence, and the organic phase is retained; the organic phase is concentrated, and an antisolvent is added to the organic phase at 20~50℃, and the temperature is slowly lowered to 0~30℃ and stirred for 1~3 h to cool and crystallize, and a solid is precipitated. The solid and liquid are separated to obtain compound lafutidine of formula 1.

[0055] In some embodiments, preferably, in step (2), after the condensation reaction is completed, the reaction solution is washed with an alkaline solution and water in sequence, and the organic phase is retained; the organic phase is concentrated, and an antisolvent is added to the organic phase at 40~50℃, and the temperature is slowly lowered to 0~10℃ and stirred for 2 h to cool and crystallize, and a solid is precipitated. The solid and liquid are separated to obtain compound lafutidine of formula 1.

[0056] In step (2), an antisolvent is added to the organic phase to precipitate the solid, the solid and liquid are separated, the solid is washed with the antisolvent and dried to obtain compound lafutidine of formula 1.

[0057] Furthermore, preferably, the present invention discloses a method for preparing lafutidine, comprising the following steps:

[0058] (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained.

[0059] ;

[0060] (2) The compound of formula 4 obtained in step (1) undergoes a condensation reaction with the compound of formula 5 to obtain lafutidine of formula 1.

[0061] ;

[0062] Wherein, R is selected from n-butyl or n-propyl;

[0063] In step (1):

[0064] The organic solvent is methanol;

[0065] The alkaline substance is any one or a combination of two of sodium hydroxide and potassium hydroxide, and the alkaline substance is added in the form of an aqueous solution. Further, the mass concentration of the alkaline substance in the aqueous solution is 3% to 10%.

[0066] The molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:2~8;

[0067] The molar ratio of the compound shown in Formula 2 to the primary amine compound is 1:18~22;

[0068] The aminolysis reaction is carried out at a temperature of 20℃~30℃.

[0069] The deprotection reaction is carried out at a temperature of 20℃~30℃.

[0070] After the deprotection reaction is completed, the organic solvent is removed by concentration, and the compound shown in Formula 4 in the reaction solution is extracted with isopropyl acetate. The organic phase is retained and washed successively with an alkaline solution and a sodium chloride solution to obtain a reaction solution containing the compound shown in Formula 4. The amount of isopropyl acetate used is based on the compound shown in Formula 2, and the mass-volume ratio of the compound shown in Formula 2 to the isopropyl acetate is 1 g: (15~25) mL.

[0071] In step (1), the mass concentration of alkaline substance in the alkaline solution is 1% to 20%, and the mass concentration of sodium chloride in the sodium chloride solution is 1% to 20%.

[0072] In some embodiments, in step (1), the washing of the organic phase is preferably performed by sequentially washing with an alkaline solution and a sodium chloride solution, which can effectively remove the impurities generated in the reaction of step (1), so that the impurities generated when the reaction solution of compound 4 participates in the subsequent reaction to prepare lafutidine are lower and the product purity is higher; the alkaline solution is water as the solvent and any one or a combination of two of sodium hydroxide and potassium hydroxide as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 15%; the sodium chloride solution is water as the solvent and sodium chloride as the solute, and the mass concentration of the solute in the solution is 1% to 20%, preferably 5% to 20%.

[0073] In some embodiments, in step (2), the ratio of the amount of compound shown in Formula 5 to the amount of compound shown in Formula 4 is calculated based on the amount of compound shown in Formula 2 used during its preparation. The molar ratio of compound shown in Formula 5 to compound shown in Formula 2 is 0.8~1.2:1.0, preferably 0.9~1.1:1.0, and more preferably 1.0:1.0.

[0074] In some embodiments, in step (2), the condensation reaction is carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably 20°C to 30°C.

[0075] In some embodiments, in step (2), the condensation reaction takes 1 to 4 hours, preferably 2 hours.

[0076] In step (2), since the reaction solution containing the compound shown in Formula 4 obtained in step (1) contains an extraction solvent, no solvent may be added in the condensation reaction; alternatively, other solvents may be added, such as organic solvents, for example, any one or a combination of aromatic solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents. Preferably, the extraction solvent is an ester solvent, more preferably, the ester solvent is any one or a combination of methyl acetate, ethyl acetate and isopropyl acetate, and even more preferably, isopropyl acetate.

[0077] In some embodiments, in step (2), after the condensation reaction is completed, the reaction solution is filtered and washed with alkaline solution and water in sequence, and the organic phase is retained; an antisolvent is added to the organic phase for cooling and crystallization, and a solid is precipitated. Solid-liquid separation is performed to obtain lafuratedin as shown in Formula 1.

[0078] The antisolvent is any one or a combination of several of methyl tert-butyl ether, n-heptane, n-hexane and isopropyl ether, preferably methyl tert-butyl ether; preferably, the organic phase is concentrated before adding the antisolvent to the organic phase, and the volume ratio of the concentrated organic phase to the antisolvent is 1:1 to 4, preferably 1:2.

[0079] In some embodiments, in step (2), the alkaline solution is water as the solvent and sodium hydroxide and potassium hydroxide as the solute, and the mass percentage concentration of the solute in the solution is 1% to 20%, preferably 5% to 15%.

[0080] In some embodiments, in step (2), after the condensation reaction is completed, the reaction solution is washed with alkaline solution and water in sequence, and the organic phase is retained; the organic phase is concentrated, and an antisolvent is added to the organic phase at 20~50℃, and the temperature is slowly lowered to 0~30℃ and stirred for 1~3 h to cool and crystallize, and a solid is precipitated. The solid and liquid are separated to obtain compound lafutidine of formula 1.

[0081] In some embodiments, preferably, in step (2), after the condensation reaction is completed, the reaction solution is washed with an alkaline solution and water in sequence, and the organic phase is retained; the organic phase is concentrated, and an antisolvent is added to the organic phase at 40~50℃, and the temperature is slowly lowered to 0~10℃ and stirred for 2 h to cool and crystallize, and a solid is precipitated. The solid and liquid are separated to obtain compound lafutidine of formula 1.

[0082] In step (2), an antisolvent is added to the organic phase to precipitate the solid, the solid and liquid are separated, the solid is washed with the antisolvent and dried to obtain compound lafutidine of formula 1.

[0083] Beneficial effects:

[0084] (1) Compared with the prior art, the preparation method of lafutidine provided by the present invention has the advantages of low production cost, good safety, high purity and suitability for industrial production.

[0085] (2) The present invention uses n-butylamine or n-propylamine to aminolyze the compound of formula 2. Both are liquids at room temperature and pressure, are not easily volatilized, have high stability, good safety and low cost. When n-butylamine or n-propylamine is used in the synthesis of lafutidine, the post-processing is simple, there is almost no residue, the yield and purity of the product are high, and it is suitable for large-scale industrial production. Attached Figure Description

[0086] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0087] Figure 1 The image shows the 1H NMR spectrum of compound 4.

[0088] Figure 2 This is a mass spectrometry data graph of compound formula 4.

[0089] Figure 3 The image shows the 1H NMR spectrum of compound lafutidine (Formula 1).

[0090] Figure 4 The image shows the carbon NMR spectrum of compound lafutidine (Formula 1).

[0091] Figure 5 The mass spectrum of compound lafutidine (Formula 1) is shown.

[0092] Figure 6 The image shows the liquid phase purity test result of lafutidine, a compound of formula 1 prepared in Example 1.

[0093] Figure 7 The image shows the liquid phase purity determination of lafutidine, the compound of formula 1 prepared in Comparative Example 1.

[0094] Figure 8 The image shows the liquid phase purity test result of lafutidine, the compound of formula 1 prepared in Example 2.

[0095] Figure 9 The image shows the liquid phase purity determination of lafutidine, the compound of formula 1 prepared in Comparative Example 2.

[0096] Figure 10 The image shows the liquid phase purity test result of lafutidine, a compound of formula 1 prepared in Example 3.

[0097] Figure 11 This is the mass spectrum of intermediate 3-1 compound from Example 1. Detailed Implementation

[0098] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0099] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0100] In this embodiment of the invention, the term "controlled internal temperature" refers to the internal temperature of the reaction.

[0101] In the embodiments of this invention, the percentages representing concentrations are all mass percentages unless otherwise specified.

[0102] In this embodiment of the invention, the purity of lafutidine was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0103] Example 1: Amine hydrolysis of n-butylamine using methanol as solvent

[0104] (1) Synthesis of compound 4:

[0105]

[0106] Compound 2 (50.00 g, 0.1 mol) and methanol (500 mL) were added to a 1000 mL three-necked flask and stirred at 25±5℃. n-Butylamine (144.11 g, 2 mol) was rapidly added dropwise to the reaction solution. The solution quickly became clear, then turbid, and then quickly cleared again. After the addition was complete, stirring was continued at 25±5℃ for 4 h to carry out the aminolysis reaction. After the aminolysis reaction was completed, NaOH aqueous solution (19.70 g NaOH dissolved in 400 mL of water) was added, and stirring was continued at 25±5℃ for 2 h to carry out the deprotection reaction. After the reaction was completed, the solution was distilled under reduced pressure at 45±5℃ until no obvious droplets dripped from the condenser, at which point the concentration was stopped. 500 mL of isopropyl acetate and 400 mL of water were added, and the mixture was stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (40.00 g NaOH dissolved in 360 mL of water) was added to the organic phase, and the mixture was stirred for 15±5 min. After stirring for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add NaCl aqueous solution (40.00 g NaCl dissolved in 360 mL of water) to the organic phase and stir for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add 500 mL of isopropyl acetate to the organic phase, and distill under reduced pressure at 45 ± 5 °C to concentrate to approximately 400 mL of the remaining reaction solution containing compound 4 for later use.

[0107] The experiment was repeated, and the compound of formula 4 was isolated, purified, and analyzed by NMR and mass spectrometry. The 1H NMR spectrum of the compound of formula 4 is shown below. Figure 1 As shown, the mass spectrometry data is as follows: Figure 2 As shown, the specific NMR and mass spectrometry data are as follows:

[0108] 1 H NMR (400MHz, d6-DMSO): δ8.05 (d, 1H), δ6.90 (d, 1H), δ6.70 (s, 1H), δ5.55~5.68 (m, 2H), δ4.82 (d, 2H), δ3.39 (s, 2H), δ3.26 (d, 2H), δ2.50 (m,4H), δ1.50 (m, 4H), δ1.38 (m, 2H). MS (m / z): 193.12[M-C4H8N+H] + .

[0109] During the aminolysis reaction, intermediate 3-1 was analyzed, MS (m / z): 465.24 [M+H] + 487.22 [M+Na] + For the specific mass spectrum, please see Figure 11 .

[0110] (2) Synthesis of compound lafutidine (Formula 1):

[0111]

[0112] Add compound 5 (30.47 g, 0.1 mol) to approximately 400 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 25±5℃ for 2 h to carry out a condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (40.00 g NaOH dissolved in 360 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (40.00 g NaOH dissolved in 360 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 400 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃, concentrate to approximately 200 mL of the remaining reaction solution, add methyl tert-butyl ether (400 mL) dropwise to the reaction solution at 45±5℃, after which a large amount of white solid precipitates, slowly cool to 0~10℃ and stir for 2 h. h, filtration, washing the filter cake with methyl tert-butyl ether, and drying the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound latfuratenil of formula 1, 37.45 g, with an overall yield of 88.10% (based on the amount of compound 2 fed) and a purity of 99.95% (see Figure 6 ).

[0113] The 1H NMR spectrum of compound lafutidine (Formula 1) is shown below. Figure 3 The carbon NMR spectrum of compound lafutidine (Formula 1) is shown below. Figure 4 The mass spectrum of compound lafutidine (Formula 1) is shown in [reference needed]. Figure 5 The liquid phase purity test chromatogram of the compound lafutidine (Formula 1) prepared in this embodiment is shown in the figure. Figure 6 The specific NMR and mass spectrometry data are shown below:

[0114] 1 H NMR (400MHz, d6-DMSO): δ8.52 (t, 1H), δ8.07 (d, 1H), δ7.69 (t, 1H), δ6.92 (d, 1H), δ6.71 (s, 1H), δ6.49 (t, 1H), δ6.45 (d, 1H), δ5.75 (m, 1H), δ5.55 (m, 1H), δ4.88 (d, 2H), δ4.35 (d, 1H), δ4.16 (d, 1H), δ3.87 (t, 2H), δ3.73 (d, 1H), δ3.55 (d, 1H), δ3.39 (s, 2H), δ2.31 (s, 4H), δ1.50 (m, 4H), δ1.38 (d, 2H). 13 C-NMR (100MHz, d6-DMSO): δ164.54, δ163.56, δ151.90, δ146.96, δ145.79, δ144.28, δ130.07, δ127.77, δ117.84, δ111.63, δ111.58, δ110.33, δ61.80, δ61.53, δ57.12, δ54.42, δ50.25, δ36.84, δ26.01, δ24.31. MS (m / z):432.17[M+H] + .

[0115] Comparative Example 1: Acetaminolysis was performed using ethylamine with ethanol as the solvent.

[0116]

[0117] (1) Synthesis of compound 4:

[0118] Compound of Formula 2 (10.00 g, 0.02 mol) and ethanol (100 mL) were added to a 500 mL three-necked flask and stirred at 25±5℃. 68% ethylamine (26.30 g, 0.4 mol) was rapidly added dropwise to the reaction solution. The solution quickly became clear, then turbid, with a large amount of white solid precipitating out. After the addition was complete, the mixture was stirred at 25±5℃ for 20 h to carry out the aminolysis reaction until the solution was clear. After the aminolysis reaction was completed, NaOH aqueous solution (7.90 g NaOH dissolved in 100 mL of water) was added, and the mixture was stirred at 25±5℃ for 2 h to carry out the deprotection reaction. After the reaction was completed, the mixture was distilled under reduced pressure at 45±5℃ until no obvious droplets dripped from the condenser. 100 mL of isopropyl acetate and 70 mL of water were added, and the mixture was stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (10.00 g NaOH dissolved in 90 mL of water) was added to the organic phase and stirred for 15±5 min. After stirring for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add NaCl aqueous solution (10.00 g NaCl dissolved in 90 mL of water) to the organic phase and stir for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add 100 mL of isopropyl acetate to the organic phase, and distill under reduced pressure at 45 ± 5 ℃ to concentrate to about 80 mL of the remaining reaction solution containing the compound of formula 4 for later use.

[0119] (2) Synthesis of compound lafutidine (Formula 1):

[0120] Add compound 5 (6.09 g, 0.02 mol) to approximately 80 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 25±5℃ for 2 h to carry out the condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (15.00 g NaOH dissolved in 135 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (15.00 g NaOH dissolved in 135 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 100 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃ and concentrate to approximately 40 mL of the remaining reaction solution. Add methyl tert-butyl ether (80 mL) dropwise to the reaction solution at 45±5℃. After the addition is complete, a large amount of white solid precipitates. Slowly cool to 0~10℃ and stir for 2 h. h, filtration, washing the filter cake with methyl tert-butyl ether, and drying the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound lafutidine of formula 1, 6.71 g, with an overall yield of 78.92% (based on the amount of compound of formula 2 fed) and a purity of 98.13% (see Figure 7 ).

[0121] Example 2: Amine hydrolysis of n-butylamine was performed using ethanol as the solvent.

[0122] The synthesis route is shown in Example 1.

[0123] (1) Synthesis of compound 4:

[0124] Compound of Formula 2 (10.00 g, 0.02 mol) and ethanol (100 mL) were added to a 500 mL three-necked flask and stirred at 25±5℃. n-Butylamine (28.82 g, 0.4 mol) was rapidly added dropwise to the reaction solution. The solution quickly became clear, then turbid, and then quickly cleared again. After the addition was complete, the mixture was stirred at 25±5℃ for 8 h to carry out the aminolysis reaction (reaction complete). After the aminolysis reaction was completed, NaOH aqueous solution (3.95 g NaOH dissolved in 80 mL of water) was added and the mixture was stirred at 25±5℃ for 2 h to carry out the deprotection reaction. After the reaction was completed, the mixture was distilled under reduced pressure at 45±5℃ until no obvious droplets dripped from the condenser, at which point the concentration was stopped. 100 mL of isopropyl acetate and 80 mL of water were added and stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) was added to the organic phase and stirred for 15±5 min. After stirring for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add NaCl aqueous solution (8.00 g NaCl dissolved in 72 mL water) to the organic phase and stir for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add 100 mL of isopropyl acetate to the organic phase, and distill under reduced pressure at 45 ± 5 °C to concentrate the mixture to approximately 80 mL of the reaction solution containing compound 4 for later use.

[0125] (2) Synthesis of compound lafutidine (Formula 1):

[0126] Add compound 5 (6.09 g, 0.02 mol) to approximately 80 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 25±5℃ for 2 h to carry out the condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 80 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃, concentrate to approximately 40 mL of the remaining reaction solution, add methyl tert-butyl ether (80 mL) dropwise to the reaction solution at 45±5℃, after which a large amount of white solid precipitates, slowly cool to 0~10℃ and stir for 2 h. h, filtration, washing the filter cake with methyl tert-butyl ether, and drying the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound lafutidine of formula 1, 7.30 g, with an overall yield of 85.88% (based on the amount of compound of formula 2 fed) and a purity of 99.94% (see Figure 8 ).

[0127] Comparative Example 2: Amine hydrolysis of ethanolamine was performed using ethanol as the solvent.

[0128]

[0129] (1) Synthesis of compound 4:

[0130] Compound of Formula 2 (99.99 g, 0.2 mol) and ethanol (1000 mL) were added to a 3000 mL three-necked flask. The mixture was stirred at 25±5℃. Ethanolamine (244.32 g, 4 mol) was rapidly added dropwise to the reaction solution. The reaction solution quickly became clear, then turbid, and then quickly became clear again. After the addition was complete, the mixture was stirred at 25±5℃ for 4.5 h to carry out the aminolysis reaction. After the aminolysis reaction was completed, NaOH aqueous solution (43.36 g NaOH dissolved in 1000 mL of water) was added, and the mixture was stirred at 25±5℃ for 3 h to carry out the deprotection reaction. After the reaction was completed, the mixture was distilled under reduced pressure at 45±5℃ until no obvious droplets fell from the condenser. The concentration was stopped, and 1000 mL of isopropyl acetate and 400 mL of water were added. The mixture was stirred for 15±5 min, allowed to stand, and separated, retaining the organic phase. NaOH aqueous solution (80.00 g NaOH dissolved in 720 mL of water) was added to the organic phase and stirred for 15±5 min. After standing for 15 minutes, allow the mixture to separate and retain the organic phase. Add NaCl aqueous solution (80.00 g NaCl dissolved in 720 mL of water) to the organic phase and stir for 15 ± 5 minutes. Allow the mixture to stand and separate and retain the organic phase. Add anhydrous sodium sulfate (200 g) to the organic phase to remove water for 8 hours. Filter and take the filtrate containing compound 4 for later use.

[0131] (2) Synthesis of compound lafutidine (Formula 1):

[0132] Compound 5 (69.23 g, 0.22 mol) was added to the filtrate containing compound 4 obtained in step (1) above, and stirred at 25±5℃ for 2 h to carry out a condensation reaction. After the reaction was completed, the insoluble matter was removed by filtration. NaOH aqueous solution (80.00 g NaOH dissolved in 720 mL water) was added to the filtrate, and the mixture was stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (80.00 g NaOH dissolved in 720 mL water) was added to the organic phase, and the mixture was stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. 800 mL of saturated saline solution was added to the organic phase, and the mixture was stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was distilled under reduced pressure at 45±5℃ and concentrated until no obvious droplets fell from the condenser. Isopropyl ether (100 mL) was added to the reaction solution at 25±5℃, and a large amount of white solid precipitated. The temperature was raised to 65±5℃ and stirred for 0.5 h. The temperature was slowly lowered to 5±5℃ and stirred for 0.5 h. After filtration, the filter cake was dried under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound lafutidine of formula 1, 70.06 g, yield 82.39%, purity 99.40% (see [link to product description]). Figure 9 ).

[0133] Example 3: Amine hydrolysis of n-propylamine was performed using ethanol as the solvent.

[0134]

[0135]

[0136] (1) Synthesis of compound 4:

[0137] Compound of Formula 2 (20.00 g, 0.04 mol) and ethanol (200 mL) were added to a 500 mL three-necked flask. The mixture was stirred at 25±5℃. Propylamine (46.59 g, 0.8 mol) was rapidly added dropwise to the reaction solution. The solution initially became clear but then cloudy. After the addition was complete, the mixture was stirred at 25±5℃ for 24 h to carry out the aminolysis reaction (reaction complete). After the aminolysis reaction, NaOH aqueous solution (7.91 g NaOH dissolved in 200 mL water) was added. An oily substance adhered to the bottom of the flask, affecting stirring. The mixture was stirred at 25±5℃ for 2 h to carry out the deprotection reaction. The reaction solution became clear. After the reaction, the mixture was distilled under reduced pressure at 45±5℃ until no obvious drops fell from the condenser. Concentration was stopped, and 200 mL of isopropyl acetate and 160 mL of water were added. The mixture was stirred for 15±5 min, allowed to stand, and separated, retaining the organic phase. NaOH aqueous solution (16.02 g NaOH dissolved in 144 mL water) was added to the organic phase. Stir for 15±5 min in 144 mL of water, let stand and separate the liquid, retaining the organic phase; add NaCl aqueous solution (16.00 g NaCl dissolved in 144 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 100 mL of isopropyl acetate to the organic phase, distill under reduced pressure at 45±5℃, and concentrate to about 160 mL of the reaction solution containing compound 4 for later use.

[0138] (2) Synthesis of compound lafutidine (Formula 1):

[0139] Add compound 5 (12.18 g, 0.04 mol) to approximately 160 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 25±5℃ for 2 h to carry out a condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (16.01 g NaOH dissolved in 144 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (16.02 g NaOH dissolved in 144 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 160 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃, concentrate to approximately 80 mL of the remaining reaction solution, add methyl tert-butyl ether (160 mL) dropwise to the reaction solution at 45±5℃, after which a large amount of white solid precipitates, slowly cool to 0~10℃ and stir for 2 h. h, filtration, washing the filter cake with methyl tert-butyl ether, and drying the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound lafutidine of formula 1, 13.64 g, with an overall yield of 80.24% (based on the amount of compound of formula 2 fed) and a purity of 99.72% (see Figure 10 ).

[0140] Example 4:

[0141] The synthesis route is shown in Example 1.

[0142] (1) Synthesis of compound 4:

[0143] Compound of Formula 2 (10.00 g, 0.02 mol) and ethanol (100 mL) were added to a 500 mL three-necked flask and stirred at 15±5℃. n-Butylamine (17.3 g, 0.24 mol) was rapidly added dropwise to the reaction solution. The solution quickly became clear, then turbid, and then quickly cleared again. After the addition was complete, the mixture was stirred at 15±5℃ for 8 h to carry out the aminolysis reaction (reaction complete). After the aminolysis reaction was completed, NaOH aqueous solution (1.98 g NaOH dissolved in 40 mL of water) was added and the mixture was stirred at 15±5℃ for 2 h to carry out the deprotection reaction. After the reaction was completed, the mixture was distilled under reduced pressure at 45±5℃ until no obvious droplets dripped from the condenser, at which point the concentration was stopped. 100 mL of isopropyl acetate and 80 mL of water were added and stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) was added to the organic phase and stirred for 15±5 min. After stirring for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add NaCl aqueous solution (8.00 g NaCl dissolved in 72 mL water) to the organic phase and stir for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add 100 mL of isopropyl acetate to the organic phase, and distill under reduced pressure at 45 ± 5 °C to concentrate the mixture to approximately 80 mL of the reaction solution containing compound 4 for later use.

[0144] (2) Synthesis of compound lafutidine (Formula 1):

[0145] Add compound 5 (4.88 g, 0.016 mol) to approximately 80 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 15±5℃ for 2 h to carry out the condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 80 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃, concentrate to approximately 40 mL of the remaining reaction solution, add n-heptane (80 mL) dropwise to the reaction solution at 45±5℃, after which a large amount of white solid precipitates, slowly cool to 0~10℃ and stir for 2 h. h, filter, wash the filter cake with n-heptane, and dry the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound latfuratedin of formula 1, 5.96 g, with an overall yield of 86.35% (based on the amount of compound 5 fed) and a purity of 99.92%.

[0146] Example 5:

[0147] The synthesis route is shown in Example 1.

[0148] (1) Synthesis of compound 4:

[0149] Compound of Formula 2 (10.00 g, 0.02 mol) and ethanol (100 mL) were added to a 500 mL three-necked flask and stirred at 35±5℃. Then, n-butylamine (36.03 g, 0.5 mol) was rapidly added dropwise to the reaction solution. The solution quickly became clear, then turbid, and then quickly cleared again. After the addition was complete, the mixture was stirred at 35±5℃ for 8 h to carry out the aminolysis reaction (reaction complete). After the aminolysis reaction was completed, NaOH aqueous solution (6.32 g NaOH dissolved in 80 mL of water) was added and the mixture was stirred at 35±5℃ for 2 h to carry out the deprotection reaction. After the reaction was completed, the mixture was distilled under reduced pressure at 45±5℃ until no obvious droplets dripped from the condenser, at which point the concentration was stopped. 100 mL of isopropyl acetate and 80 mL of water were added and stirred for 15±5 min. The mixture was allowed to stand and separated, retaining the organic phase. NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) was added to the organic phase and stirred for 15±5 min. After stirring for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add NaCl aqueous solution (8.00 g NaCl dissolved in 72 mL water) to the organic phase and stir for 15 ± 5 min, allow the mixture to stand and separate the liquids, retaining the organic phase; add 100 mL of isopropyl acetate to the organic phase, and distill under reduced pressure at 45 ± 5 °C to concentrate the mixture to approximately 80 mL of the reaction solution containing compound 4 for later use.

[0150] (2) Synthesis of compound lafutidine (Formula 1):

[0151] Add compound 5 (7.31 g, 0.024 mol) to approximately 80 mL of the reaction solution containing compound 4 obtained in step (1) above and stir at 35±5℃ for 2 h to carry out the condensation reaction. After the reaction is completed, filter to remove insoluble matter, add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the filtrate, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; add 80 mL of water to the organic phase, stir for 15±5 min, let stand and separate the liquid, retaining the organic phase; distill the organic phase under reduced pressure at 45±5℃, concentrate to approximately 40 mL of the remaining reaction solution, add n-hexane (80 mL) dropwise to the reaction solution at 45±5℃, after which a large amount of white solid precipitates, slowly cool to 0~10℃ and stir for 2 h. h, filter, wash the filter cake with n-hexane, and dry the solid under reduced pressure at 45±5℃ to obtain a white powdery solid, namely compound latfuratedin of formula 1, 7.33 g, with an overall yield of 86.23% (based on the amount of compound 2 fed) and a purity of 99.93%.

[0152] Example 6: Amine hydrolysis of n-butylamine using ethanol as solvent

[0153] The synthesis route is shown in Example 1.

[0154] (1) Synthesis of compound 4:

[0155] The reaction materials and conditions are basically the same as in step (1) of Example 2. The difference is that the post-treatment after the aminolysis reaction is different. Specifically, after the aminolysis reaction, NaOH aqueous solution (3.95 g NaOH dissolved in 80 mL of water) is added and stirred at 25±5℃ for 2 h to carry out the deprotection reaction. After the reaction is completed, the mixture is distilled under reduced pressure at 45±5℃ until no obvious droplets fall from the condenser and the concentration is stopped. 100 mL of ethyl acetate and 80 mL of water are added and stirred for 15±5 min. The mixture is allowed to stand and the liquid is separated, retaining the organic phase. NaOH aqueous solution (8.00 g NaOH dissolved in 72 mL of water) is added to the organic phase and stirred for 15±5 min. The mixture is allowed to stand and the liquid is separated, retaining the organic phase. NaCl aqueous solution (8.00 g NaCl dissolved in 72 mL of water) is added to the organic phase and stirred for 15±5 min. The mixture is allowed to stand and the liquid is separated, retaining the organic phase. 100 mL of ethyl acetate is added to the organic phase and the mixture is distilled under reduced pressure at 45±5℃ and concentrated to about 80 mL of the reaction solution containing the compound of formula 4 for later use.

[0156] (2) Synthesis of compound lafutidine (Formula 1):

[0157] Except for the reaction solution of compound 4, the other materials and conditions are the same as in step (2) of Example 2, and 6.88 g of compound 1 lafutidine is obtained. The total yield of the two steps is 80.94% (based on the amount of compound 2 added) and the purity is 98.57%.

[0158] This invention provides a method and approach for preparing lafutidine. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing a compound as shown in Formula 4, characterized in that, Includes the following steps: (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained. ； R is selected from n-butyl or n-propyl.

2. A method for preparing lafutidine, characterized in that, Includes the following steps: (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained. ； (2) The compound of formula 4 obtained in step (1) undergoes a condensation reaction with the compound of formula 5 to obtain lafutidine of formula 1. ； R is selected from n-butyl or n-propyl.

3. The preparation method according to claim 1 or claim 2, characterized in that, In step (1), the organic solvent is an alcohol solvent; preferably, the alcohol solvent is any one or a combination of methanol, ethanol and isopropanol; more preferably, the alcohol solvent is any one or a combination of methanol and ethanol; even more preferably, the alcohol solvent is methanol.

4. The preparation method according to claim 1 or claim 2, characterized in that, In step (1), the alkaline substance is any one or a combination of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the alkaline substance is sodium hydroxide; more preferably, the alkaline substance is added in the form of an aqueous solution, and further preferably, the mass concentration of the alkaline substance in the aqueous solution is 1%~20%, preferably 3%~10%; the molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:1~20, preferably 1:2~8.

5. The preparation method according to claim 1 or claim 2, characterized in that, In step (1), the molar ratio of the compound shown in Formula 2 to the primary amine compound is 1:10~30, preferably 1:18~22, and more preferably 1:

20.

6. The preparation method according to claim 1 or claim 2, characterized in that, In step (1), the aminolysis reaction is carried out at a temperature of 0℃~60℃, preferably 10℃~40℃, and more preferably 20℃~30℃; the deprotection reaction is carried out at a temperature of 0℃~60℃, preferably 10℃~40℃, and more preferably 20℃~30℃.

7. The preparation method according to claim 1 or claim 2, characterized in that, In step (1), after the deprotection reaction is completed, the organic solvent is concentrated and removed, and the compound shown in Formula 4 in the reaction solution is extracted with an extraction solvent. The organic phase is retained and washed to obtain a reaction solution containing the compound shown in Formula 4. The extraction solvent is any one or a combination of several of aromatic solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents; preferably, the extraction solvent is an ester solvent; more preferably, the ester solvent is any one or a combination of several of methyl acetate, ethyl acetate and isopropyl acetate, and even more preferably isopropyl acetate; The amount of the extraction solvent, based on the compound shown in Formula 2, is 1 g: (5~30) mL, preferably 1 g: (15~25) mL, and more preferably 1 g: 20 mL. The washing organic phase is selected from those washed sequentially with an alkaline substance solution and a sodium chloride solution; further, the mass concentration of the alkaline substance in the alkaline substance solution is 1%~20%, and the mass concentration of sodium chloride in the sodium chloride solution is 1%~20%.

8. The preparation method according to claim 2, characterized in that, In step (2), the ratio of the amount of compound shown in Formula 5 to the amount of compound shown in Formula 4 is calculated based on the amount of compound shown in Formula 2 used during its preparation. The molar ratio of compound shown in Formula 5 to compound shown in Formula 2 is 0.8~1.2:1.0, preferably 0.9~1.1:1.0, and more preferably 1.0:1.

0.

9. The preparation method according to claim 2, characterized in that, In step (2), the condensation reaction is carried out at a temperature of 0℃~60℃, preferably 10℃~40℃, and more preferably 20℃~30℃. After the condensation reaction is completed, the reaction solution is filtered and washed with alkaline solution and water in sequence, and the organic phase is retained. An antisolvent is added to the organic phase for cooling and crystallization, and a solid is precipitated. The solid and liquid are separated to obtain lafutidine as shown in Formula 1. The antisolvent is any one or a combination of several of methyl tert-butyl ether, n-heptane, n-hexane and isopropyl ether, preferably methyl tert-butyl ether; preferably, the organic phase is concentrated before adding the antisolvent to the organic phase, and the volume ratio of the concentrated organic phase to the antisolvent is 1:1 to 4, preferably 1:

2.

10. A method for preparing lafutidine, characterized in that, Includes the following steps: (1) The compound shown in Formula 2 and the primary amine compound shown in Formula RNH2 were subjected to an aminolysis reaction in an organic solvent. Then, an alkaline substance was added to the resulting reaction solution to continue the deprotection reaction, and the compound shown in Formula 4 was obtained. ； (2) The compound of formula 4 obtained in step (1) undergoes a condensation reaction with the compound of formula 5 to obtain lafutidine of formula 1. ； Wherein, R is selected from n-butyl or n-propyl; In step (1): The organic solvent is methanol; The alkaline substance is any one or a combination of two of sodium hydroxide and potassium hydroxide, and the alkaline substance is added in the form of an aqueous solution. Further, the mass concentration of the alkaline substance in the aqueous solution is 3% to 10%. The molar ratio of the compound shown in Formula 2 to the alkaline substance is 1:2~8; The molar ratio of the compound shown in Formula 2 to the primary amine compound is 1:18~22; The aminolysis reaction is carried out at a temperature of 20℃~30℃. The deprotection reaction is carried out at a temperature of 20℃~30℃. After the deprotection reaction is completed, the organic solvent is removed by concentration, and the compound shown in Formula 4 in the reaction solution is extracted with isopropyl acetate. The organic phase is retained and washed successively with an alkaline solution and a sodium chloride solution to obtain a reaction solution containing the compound shown in Formula 4. The amount of isopropyl acetate used is based on the compound shown in Formula 2, and the mass-volume ratio of the compound shown in Formula 2 to the isopropyl acetate is 1 g: (15~25) mL.

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