A synthetic process of roxatidine intermediate 3

Abstract

The present invention provides a synthesis process of a roxatidine intermediate 3, comprising the following steps: dissolving m-hydroxybenzaldehyde in water, adding a sodium hydroxide aqueous solution, concentrating under reduced pressure after post-treatment, and filtering until there is substantially no droplet, to obtain a filter cake of sodium m-hydroxybenzaldehyde; using 3-chloropropylamine hydrochloride as a starting material, stirring and reacting with di-tert-butyl dicarbonate in a dichloromethane system under alkaline conditions in the presence of sodium hydroxide to obtain BOC-3-chloropropylamine; adding sodium m-hydroxybenzaldehyde, tetrabutylammonium bromide and purified water to the BOC-3-chloropropylamine prepared in step (2) to obtain RXTA4; adding methanol to the RXTA4 obtained in step (3), stirring until the system is dissolved and clear, slowly adding potassium borohydride in batches, and then adding piperidine to finally obtain the roxatidine intermediate 3. The synthesis process of a roxatidine intermediate 3 proposed by the present invention has mild reaction temperature, good reaction selectivity and high synthesis yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a synthesis process of a roxatidine intermediate 3. Background Art

[0002] In the field of pharmaceutical chemistry, roxatidine, as an important histamine H2 receptor antagonist, is widely used in the treatment of upper gastrointestinal bleeding caused by peptic ulcer, acute stress ulcer and hemorrhagic gastritis. However, in the synthesis process of roxatidine, the preparation process of its key intermediate RXTA3 has always been one of the key factors restricting its large-scale production and application. The traditional RXTA3 synthesis method has problems such as high raw material cost, harsh reaction conditions, many by-products and low yield. Therefore, it is particularly important to develop an efficient and low-cost RXTA3 synthesis process.

[0003] In the prior art, m-hydroxybenzaldehyde is mainly used as a raw material to synthesize intermediate 3 (ie, RXTA3). The main disadvantage of this method is that quaternary ammonium salt impurities are difficult to effectively remove during the synthesis process, and the by-products formed by the condensation of 3-chloropropylamine itself cannot be well controlled, and the synthesis yield is also affected to varying degrees.

[0004] Based on this, the present invention provides a synthesis process of roxatidine intermediate 3. Summary of the invention

[0005] The purpose of the present invention is to provide a synthesis process of a roxatidine intermediate 3, which has mild reaction temperature, good reaction selectivity and high synthesis yield.

[0006] The present invention provides a synthesis process of roxatidine intermediate 3, comprising the following steps: (1) m-Hydroxybenzaldehyde is dissolved in purified water, and a 30% sodium hydroxide aqueous solution is slowly added dropwise. After post-treatment, the purified water is concentrated under reduced pressure to obtain half of the total amount of purified water added, and the temperature is lowered to 0°C-5°C, and filtered until there is almost no droplet, to obtain a filter cake of sodium m-hydroxybenzaldehyde; (2) 3-chloropropylamine hydrochloride is used as a starting material, and reacts with di-tert-butyl dicarbonate in a dichloromethane system under alkaline conditions in the presence of sodium hydroxide, and stirred to obtain BOC-3-chloropropylamine; (3) sodium m-hydroxybenzaldehyde, tetrabutylammonium bromide and purified water are added to the BOC-3-chloropropylamine prepared in step (2), the temperature is raised to 45°C-50°C, and the reaction is refluxed for 11-13 hours. The reaction is stopped when the sodium m-hydroxybenzaldehyde is less than 5%, and the system temperature is lowered to 25°C-30°C with continuous stirring. The system is then allowed to stand for stratification, the organic layer is washed with water, and the organic layer is concentrated to dryness under reduced pressure to obtain RXTA4; (4) Methanol was added to the RXTA4 obtained in step (3), and the mixture was stirred until the system was dissolved. The temperature of the system was controlled between 0°C and 5°C, potassium borohydride was slowly added in batches, and then piperidine was added. The temperature of the system was maintained at -5°C to 5°C for insulation reaction. After the reaction was completed, 1% dilute hydrochloric acid was used to quench the reaction in the reaction solution, and the pH value of the system was neutralized to between 7 and 8 with 5% sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure until there was no flow, purified water was added, stirred and slurried, filtered, and dried under reduced pressure to obtain roxatidine intermediate 3.

[0007] Furthermore, the temperature of the purified water in step (1) is 90°C-95°C.

[0008] Furthermore, in step (1), the weight ratio of hydroxybenzaldehyde, purified water and sodium hydroxide aqueous solution is (18-22): (55-65): (20-24).

[0009] Furthermore, after the sodium hydroxide aqueous solution is added dropwise in step (1), the reaction is carried out at 90° C. to 95° C. for 55-65 minutes.

[0010] Furthermore, in step (2), the weight ratio of 3-chloropropylamine hydrochloride, sodium hydroxide, dichloromethane and di-tert-butyl dicarbonate is (9-11): (4-5): (450-550): (20-24).

[0011] Furthermore, the stirring reaction in step (2) is carried out at a temperature of 20°C-35°C and for a time of 1.5-2.5 hours.

[0012] Furthermore, in step (3), the weight ratio of BOC-3-chloropropylamine, sodium m-hydroxybenzaldehyde, tetrabutylammonium bromide and purified water is 10:(10-12):(0.11-0.13):(45-55).

[0013] Furthermore, in step (4), the weight ratio of methanol, potassium borohydride and piperidine is (450-550):(8-12):(8-9).

[0014] Furthermore, in step (4), the beating temperature is 25°C-30°C and the beating time is 55-65 minutes.

[0015] Furthermore, the conditions for reduced pressure drying in step (4) include: internal temperature <50°C, vacuum degree ≥-0.09MPa, and reduced pressure drying time of 22-26h.

[0016] The beneficial effects of the present invention are: In the process of the present invention, m-hydroxybenzaldehyde and sodium hydroxide are used to prepare sodium m-hydroxybenzaldehyde; 3-chloropropylamine hydrochloride is used as a starting material to react with di-tert-butyl dicarbonate to obtain a protective group to obtain BOC-3-chloropropylamine; sodium m-hydroxybenzaldehyde and compound B are reacted with tetrabutylammonium bromide to obtain sodium m-BOC-3-chloropropylaminobenzaldehyde; RXTA4 is reacted with piperidine and simultaneously reduced to remove the protective group to obtain roxatidine intermediate 3. The advantages are mild reaction temperature, good reaction selectivity and high synthesis yield.

[0017] In the present invention, 3-chloropropylamine is used as a starting material for the reaction, and di-tert-butyl dicarbonate is introduced as a protective agent to ensure its chemical stability during the reaction. Then, a heterogeneous catalytic reaction is carried out with sodium salt of m-hydroxybenzaldehyde under low temperature conditions to effectively inhibit the generation of imine impurities, thereby ensuring high selectivity of the reaction and high purity of the product. In addition, RXTA3 is successfully synthesized through the addition reaction of piperidine and aldehyde groups and a reduction step, which not only avoids the self-condensation problem of 3-chloropropylamine, but also cleverly avoids the generation of quaternary ammonium salt impurities. The method not only improves the quality of the product, but also significantly improves the yield of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0019] Figure 1 is the HPLC detection spectrum of the roxatidine intermediate 3 prepared in Example 1; Figure 2 is the HPLC detection spectrum of the roxatidine intermediate 3 prepared in Example 2; Figure 3 This is the HPLC detection spectrum of the roxatidine intermediate 3 prepared in Example 3. DETAILED DESCRIPTION

[0020] The technical scheme of the present invention is described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It should be noted that the raw materials can be obtained commercially.

[0021] The present invention provides a synthesis process of roxatidine intermediate 3, comprising the following steps: (1) Place 18-22g of m-hydroxybenzaldehyde in a 200mL four-necked glass reaction bottle, add 55-65g of purified water, stir and heat until the system material is dissolved; continue stirring and heat to 90℃-95℃, slowly drop 21.7g of 30% sodium hydroxide aqueous solution; after the drop is completed, keep the temperature at 90℃-95℃ for 55-65min; concentrate under reduced pressure to remove half of the total amount of purified water added, cool to 0℃-5℃, and filter until there is almost no droplets; The reaction equation is as follows:

[0022] (2) Add 9-11 g 3-chloropropylamine hydrochloride, 4-5 g sodium hydroxide and 450-550 g dichloromethane to a 1000 mL four-necked glass reaction bottle; after the addition, continue to add 20-24 g di-tert-butyl dicarbonate while stirring, maintain the system temperature between 20°C and 35°C, and keep the temperature for 1.5-2.5 hours to obtain BOC-3-chloropropylamine, which will be used in the next step; The reaction equation is as follows:

[0023] (3) Add 10-12 g of sodium m-hydroxybenzaldehyde, 0.11-0.13 g of tetrabutylammonium bromide and 45-55 g of purified water to 10 g of BOC-3-chloropropylamine prepared in step (2), stir and heat to 45°C-50°C, reflux and react for 11-13 hours, until the sodium m-hydroxybenzaldehyde is less than 5%, and stop the reaction; continue stirring and lower the system temperature to 25°C-30°C, let stand for 25-35 minutes, collect the upper aqueous layer for treatment; add 45-55 g of purified water to the lower organic layer, stir for 25-35 minutes, let stand for 25-35 minutes, collect the upper aqueous layer for treatment; reduce the pressure on the organic layer and concentrate to dryness to obtain RXTA4, which is used in the next step; The reaction equation is as follows:

[0024] (4) Add 450-550 g of methanol to the RXTA4 prepared in step (3), stir until the system material is dissolved, control the system temperature between 0°C and 5°C, slowly add 8-12 g of potassium borohydride in batches while stirring, and continue to add 8-9 g of piperidine after the addition; maintain the system temperature between -5°C and 5°C, keep the reaction warm for 3-5 hours, and the reaction is completed; continue to stir, control the system temperature between 0°C and 5°C, and slowly add 120-130 mL Stir 1% dilute hydrochloric acid aqueous solution for 25-35min to quench the reaction; add 28-32g of 5% sodium bicarbonate aqueous solution with a mass fraction while continuing to stir, and adjust the system pH to between 7-8; maintain the system temperature <45℃, vacuum degree ≥-0.09MPa, and concentrate under reduced pressure until there is no flow, which is considered to be the end of reduced pressure concentration; add 250-350g of purified water to the system, maintain the system temperature between 25℃-30℃, continue stirring and beating for 55-65min, filter to obtain the wet product of RXTA3 intermediate, dry under reduced pressure for 22-26h at an internal temperature <50℃ and a vacuum degree ≥-0.09MPa, and take samples for infrared dry and wet detection to constant weight to obtain the dry product of RXTA3 intermediate.

[0025] The reaction equation is as follows:

[0026] In step (4), the 1% dilute hydrochloric acid quenching reaction system is reacted with excess potassium borohydride, and the reaction equation is: KBH4 + 3H2O + HCl → KCl + H3BO3 + 4H2↑; In step (4), 5% sodium bicarbonate solution is used to wash and neutralize the pH value of the system, and the reaction equation is: .

[0027] The present invention will be further explained below with examples: Example

[0028] This embodiment provides a synthesis process of roxatidine intermediate 3, the steps comprising: (1) Place 20 g of m-hydroxybenzaldehyde in a 200 mL four-necked glass reaction bottle, add 60 g of purified water, stir and heat until the system material is dissolved; continue stirring and heat to 92°C, slowly drop 21.7 g of 30% sodium hydroxide aqueous solution; after the dropwise addition, keep the temperature at 92°C for 60 min; concentrate under reduced pressure to remove half of the total amount of purified water added, cool to 2°C, and filter until there is almost no droplets, to obtain 18 g of sodium m-hydroxybenzaldehyde wet product as a filter cake; The preparation method of 30% sodium hydroxide aqueous solution is as follows: add 6.5g sodium hydroxide to 15.2g purified water, stir and dissolve, and then set aside; (2) Add 10 g of 3-chloropropylamine hydrochloride, 4.5 g of sodium hydroxide and 500 g of dichloromethane to a 1000 mL four-necked glass reaction bottle; after the addition, add 22 g of di-tert-butyl dicarbonate while stirring, maintain the system temperature at 28°C, and keep the reaction warm for 2 hours to obtain BOC-3-chloropropylamine; (3) Add 10 g of sodium m-hydroxybenzaldehyde to the BOC-3-chloropropylamine prepared in step (2), i.e., the weight ratio of sodium m-hydroxybenzaldehyde to 3-chloropropylamine hydrochloride is 1:1; 0.12 g of tetrabutylammonium bromide and 50 g of purified water, stir and heat to 47°C, reflux and react for 12 hours, and when the sodium m-hydroxybenzaldehyde is less than 5%, the reaction is stopped; continue stirring to reduce the system temperature to 27°C, let stand for 30 minutes, and collect the upper aqueous layer for treatment; add 50 g of purified water to the lower organic layer, stir for 30 minutes, let stand for 30 minutes, and collect the upper aqueous layer for treatment; concentrate the organic layer under reduced pressure to dryness to obtain RXTA4; (4) Add 500 g of methanol to the RXTA4 prepared in step (3), stir until the system material is dissolved, control the system temperature between 0°C and 5°C, slowly add 10 g of potassium borohydride in batches while stirring, and continue to add 8.5 g of piperidine; maintain the system temperature between -5°C and 5°C, keep warm and react for 4 hours, and the reaction is completed; continue to stir, control the system temperature between 0°C and 5°C, slowly add 125 mL of 1% dilute hydrochloric acid aqueous solution and stir for 30 minutes to quench the reaction; continue to stir and add 30 g 5% sodium bicarbonate aqueous solution, adjust the system pH to between 7 and 8; maintain the system temperature <45°C, vacuum degree ≥-0.09MPa, and concentrate under reduced pressure until there is no flow, which is considered to be the end of reduced pressure concentration; add 300g purified water to the system, maintain the system temperature between 25°C and 30°C, continue stirring and beating for 1 hour, filter to obtain the wet product of RXTA3 intermediate, dry under reduced pressure for 24h at an internal temperature <50°C and vacuum degree ≥-0.09MPa, and take samples for infrared dry and wet detection to constant weight to obtain the dry product of RXTA3 intermediate.

[0029] In this example, 6.6 g of RXTA3 intermediate was obtained, which was an off-white crystalline powder with a purity of 98.340%. The HPLC detection spectrum was as follows: Figure 1 shown. Example

[0030] This embodiment provides a synthesis process of roxatidine intermediate 3, the steps comprising: (1) Place 20 g of m-hydroxybenzaldehyde in a 200 mL four-necked glass reaction bottle, add 60 g of purified water, stir and heat until the system material is dissolved; continue stirring and heat to 92°C, slowly drop 21.7 g of 30% sodium hydroxide aqueous solution; after the dropwise addition, keep the temperature at 92°C for 60 min; concentrate under reduced pressure to remove half of the total amount of purified water added, cool to 2°C, and filter until there is almost no droplets, to obtain 18 g of sodium m-hydroxybenzaldehyde wet product as a filter cake; The preparation method of 30% sodium hydroxide aqueous solution is as follows: add 6.5g sodium hydroxide to 15.2g purified water, stir and dissolve, and then set aside; (2) Add 10 g of 3-chloropropylamine hydrochloride, 4.5 g of sodium hydroxide and 500 g of dichloromethane to a 1000 mL four-necked glass reaction bottle; after the addition, add 22 g of di-tert-butyl dicarbonate while stirring, maintain the system temperature at 28°C, and keep the reaction warm for 2 hours to obtain BOC-3-chloropropylamine; (3) Add 11 g of sodium m-hydroxybenzaldehyde to the BOC-3-chloropropylamine prepared in step (2), i.e., the weight ratio of sodium m-hydroxybenzaldehyde to 3-chloropropylamine hydrochloride is 1.1:1; 0.12 g of tetrabutylammonium bromide and 50 g of purified water, stir and heat to 47°C, reflux and react for 12 hours, and stop the reaction until the sodium m-hydroxybenzaldehyde is less than 5%; continue stirring to lower the system temperature to 27°C, let stand for 30 minutes, and collect the upper aqueous layer for treatment; add 50 g of purified water to the lower organic layer, stir for 30 minutes, let stand for 30 minutes, and collect the upper aqueous layer for treatment; concentrate the organic layer under reduced pressure to dryness to obtain RXTA4; (4) Add 500 g of methanol to the RXTA4 prepared in step (3), stir until the system material is dissolved, control the system temperature between 0°C and 5°C, slowly add 10 g of potassium borohydride in batches while stirring, and continue to add 8.5 g of piperidine; maintain the system temperature between -5°C and 5°C, keep warm and react for 4 hours, and the reaction is completed; continue to stir, control the system temperature between 0°C and 5°C, slowly add 125 mL of 1% dilute hydrochloric acid aqueous solution and stir for 30 minutes to quench the reaction; continue to stir and add 30 g 5% sodium bicarbonate aqueous solution, adjust the system pH to between 7 and 8; maintain the system temperature <45°C, vacuum degree ≥-0.09MPa, and concentrate under reduced pressure until there is no flow, which is considered to be the end of reduced pressure concentration; add 300g purified water to the system, maintain the system temperature between 25°C and 30°C, continue stirring and beating for 1 hour, filter to obtain the wet product of RXTA3 intermediate, dry under reduced pressure for 24h at an internal temperature <50°C and vacuum degree ≥-0.09MPa, and take samples for infrared dry and wet detection to constant weight to obtain the dry product of RXTA3 intermediate.

[0031] Weight ratio in tep3 = sodium m-hydroxybenzaldehyde: 3-chloropropylamine hydrochloride = 1.1:1 (i.e. 11g sodium m-hydroxybenzaldehyde) In this example, 7.0 g of RXTA3 intermediate was obtained, which was an off-white crystalline powder with a purity of 99.947%; the HPLC detection spectrum was as follows: Figure 2 shown. Example

[0032] This embodiment provides a synthesis process of roxatidine intermediate 3, the steps comprising: (1) Place 20 g of m-hydroxybenzaldehyde in a 200 mL four-necked glass reaction bottle, add 60 g of purified water, stir and heat until the system material is dissolved; continue stirring and heat to 92°C, slowly drop 21.7 g of 30% sodium hydroxide aqueous solution; after the dropwise addition, keep the temperature at 92°C for 60 min; concentrate under reduced pressure to remove half of the total amount of purified water added, cool to 2°C, and filter until there is almost no droplets, to obtain 18 g of sodium m-hydroxybenzaldehyde wet product as a filter cake; The preparation method of 30% sodium hydroxide aqueous solution is as follows: add 6.5g sodium hydroxide to 15.2g purified water, stir and dissolve, and then set aside; (2) Add 10 g of 3-chloropropylamine hydrochloride, 4.5 g of sodium hydroxide and 500 g of dichloromethane to a 1000 mL four-necked glass reaction bottle; after the addition, add 22 g of di-tert-butyl dicarbonate while stirring, maintain the system temperature at 28°C, and keep the reaction warm for 2 hours to obtain BOC-3-chloropropylamine; (3) Add 12 g of sodium m-hydroxybenzaldehyde to the BOC-3-chloropropylamine prepared in step (2), i.e., the weight ratio of sodium m-hydroxybenzaldehyde to 3-chloropropylamine hydrochloride is 1.2:1; 0.12 g of tetrabutylammonium bromide and 50 g of purified water, stir and heat to 47°C, reflux and react for 12 hours, and stop the reaction until the sodium m-hydroxybenzaldehyde is less than 5%; continue stirring to lower the system temperature to 27°C, let stand for 30 minutes, and collect the upper aqueous layer for treatment; add 50 g of purified water to the lower organic layer, stir for 30 minutes, let stand for 30 minutes, and collect the upper aqueous layer for treatment; concentrate the organic layer under reduced pressure to dryness to obtain RXTA4; (4) Add 500 g of methanol to the RXTA4 prepared in step (3), stir until the system material is dissolved, control the system temperature between 0°C and 5°C, slowly add 10 g of potassium borohydride in batches while stirring, and continue to add 8.5 g of piperidine; maintain the system temperature between -5°C and 5°C, keep warm and react for 4 hours, and the reaction is completed; continue to stir, control the system temperature between 0°C and 5°C, slowly add 125 mL of 1% dilute hydrochloric acid aqueous solution and stir for 30 minutes to quench the reaction; continue to stir and add 30 g 5% sodium bicarbonate aqueous solution, adjust the system pH to between 7 and 8; maintain the system temperature <45°C, vacuum degree ≥-0.09MPa, and concentrate under reduced pressure until there is no flow, which is considered to be the end of reduced pressure concentration; add 300g purified water to the system, maintain the system temperature between 25°C and 30°C, continue stirring and beating for 1 hour, filter to obtain the wet product of RXTA3 intermediate, dry under reduced pressure for 24h at an internal temperature <50°C and vacuum degree ≥-0.09MPa, and take samples for infrared dry and wet detection to constant weight to obtain the dry product of RXTA3 intermediate.

[0033] In this example, 6.9 g of RXTA3 intermediate was obtained, which was an off-white crystalline powder with a purity of 99.903%. The HPLC detection spectrum was as follows: Figure 3 shown.

[0034] The applicant declares that the present invention illustrates the product and detailed preparation method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned product and detailed preparation method, that is, it does not mean that the present invention must rely on the above-mentioned product and detailed preparation method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention and addition of auxiliary materials, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0035] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details in the above embodiments, and the technical solution of the present invention can be subjected to a variety of simple modifications within the technical concept of the present invention. These simple modifications all belong to the protection scope of the present invention.

[0036] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0037] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A synthesis process of roxatidine intermediate 3, characterized in that the steps include: (1) m-Hydroxybenzaldehyde is dissolved in purified water, and a 30% sodium hydroxide aqueous solution is slowly added dropwise. After post-treatment, the purified water is concentrated under reduced pressure to obtain half of the total amount of purified water added, and the temperature is lowered to 0°C-5°C, and filtered until there is almost no droplet, to obtain a filter cake of sodium m-hydroxybenzaldehyde; (2) 3-chloropropylamine hydrochloride is used as a starting material, and reacts with di-tert-butyl dicarbonate in a dichloromethane system under alkaline conditions in the presence of sodium hydroxide, and stirred to obtain BOC-3-chloropropylamine; (3) sodium m-hydroxybenzaldehyde, tetrabutylammonium bromide and purified water are added to the BOC-3-chloropropylamine prepared in step (2), the temperature is raised to 45°C-50°C, and the reaction is refluxed for 11-13 hours. The reaction is stopped when the sodium m-hydroxybenzaldehyde is less than 5%, and the system temperature is lowered to 25°C-30°C with continuous stirring. The system is then allowed to stand for stratification, the organic layer is washed with water, and the organic layer is concentrated to dryness under reduced pressure to obtain RXTA4; (4) Methanol was added to the RXTA4 obtained in step (3), and the mixture was stirred until the system was dissolved. The temperature of the system was controlled between 0°C and 5°C, potassium borohydride was slowly added in batches, and then piperidine was added. The temperature of the system was maintained at -5°C to 5°C for insulation reaction. After the reaction was completed, 1% dilute hydrochloric acid was used to quench the reaction in the reaction solution, and the pH value of the system was neutralized to between 7 and 8 with 5% sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure until there was no flow, purified water was added, stirred and slurried, filtered, and dried under reduced pressure to obtain roxatidine intermediate 3.

2. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, The temperature of the purified water in step (1) is 90°C-95°C.

3. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, In the step (1), the weight ratio of hydroxybenzaldehyde, purified water and sodium hydroxide aqueous solution is (18-22): (55-65): (20-24).

4. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, After the sodium hydroxide aqueous solution is added dropwise in step (1), the reaction is carried out at 90° C. to 95° C. for 55 to 65 minutes.

5. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, In the step (2), the weight ratio of 3-chloropropylamine hydrochloride, sodium hydroxide, dichloromethane and di-tert-butyl dicarbonate is (9-11): (4-5): (450-550): (20-24).

6. A synthesis process for roxatidine intermediate 3 according to claim 1, characterized in that, The stirring reaction in step (2) is carried out at a temperature of 20°C-35°C and for a time of 1.5-2.5 hours.

7. A synthesis process for roxatidine intermediate 3 according to claim 1, characterized in that, In the step (3), the weight ratio of BOC-3-chloropropylamine, sodium m-hydroxybenzaldehyde, tetrabutylammonium bromide and purified water is 10: (10-12): (0.11-0.13): (45-55).

8. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, In the step (4), the weight ratio of methanol, potassium borohydride and piperidine is (450-550):(8-12):(8-9).

9. A synthesis process for a roxatidine intermediate 3 according to claim 1, characterized in that, The beating temperature in step (4) is 25°C-30°C and the beating time is 55-65 minutes.

10. A synthesis process of roxatidine intermediate 3 according to claim 1, characterized in that, The conditions for reduced pressure drying in step (4) include: internal temperature <50°C, vacuum degree ≥-0.09MPa, and reduced pressure drying time of 22-26h.

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