阅读说明：本技术 一种合成5-羟色胺己二酸盐的方法 (Method for synthesizing 5-hydroxytryptamine adipate ) 是由 李迁 田俊波 杨志彬 张犇 崔金旺 田昊博 邢瑞静 赵泽佳 贾博硕 于 2021-10-29 设计创作，主要内容包括：本发明涉及药物化学合成技术领域,提出了一种合成5-羟色胺己二酸盐的方法,包括以下步骤：S1、将5-羟色胺盐酸盐与有机醇水溶液搅拌溶解；S2、滴加氢氧化钠溶液至pH＝8±0.5,继续搅拌；S3、控制温度,滴加己二酸,并继续搅拌；S4、后处理。通过上述技术方案,解决了现有技术无法合成5-羟色胺己二酸盐的问题。(The invention relates to the technical field of pharmaceutical chemistry synthesis, and provides a method for synthesizing 5-hydroxytryptamine adipate, which comprises the following steps: s1, stirring and dissolving the 5-hydroxytryptamine hydrochloride and the organic alcohol aqueous solution; s2, dropwise adding a sodium hydroxide solution until the pH value is 8 +/-0.5, and continuously stirring; s3, controlling the temperature, dropwise adding adipic acid, and continuously stirring; and S4, post-processing. By adopting the technical scheme, the problem that 5-hydroxytryptamine adipate cannot be synthesized in the prior art is solved.)

1. A method for synthesizing 5-hydroxytryptamine adipate, comprising the steps of:

s1, stirring and dissolving the 5-hydroxytryptamine hydrochloride and the organic alcohol aqueous solution;

s2, dropwise adding a sodium hydroxide solution until the pH value is 8 +/-0.5, and continuously stirring;

s3, controlling the temperature, dropwise adding adipic acid, and continuously stirring;

and S4, post-processing.

2. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the mass concentration of the organic alcohol aqueous solution is 40% -50%, the weight ratio of the organic alcohol aqueous solution to 5-hydroxytryptamine hydrochloride is 8:1-10:1, and the organic alcohol aqueous solution is one of ethanol aqueous solution, methanol aqueous solution and isopropanol aqueous solution.

3. The method of synthesizing 5-hydroxytryptamine adipate as claimed in claim 2, wherein said aqueous organic alcohol solution is an aqueous ethanol solution.

4. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the mass concentration of the sodium hydroxide solution in the step S2 is 10% -15%.

5. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the temperature is controlled to 20-30 ℃ during the dropping and continuous stirring in step S2.

6. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the molar ratio of adipic acid to 5-hydroxytryptamine hydrochloride in step S3 is 1.1:1-1.2: 1.

7. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the temperature in step S3 is controlled to 15-25 ℃.

8. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein in the step S3, the stirring is continued for 30-35 min.

9. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 1, wherein the step S4 comprises vacuum distillation, cooling, stirring, suction filtration, washing, and drying.

10. The method for synthesizing 5-hydroxytryptamine adipate as claimed in claim 9, wherein in the step S4, the specific conditions of reduced pressure distillation are as follows: under the vacuum of-0.09 MPa to-0.095 MPa, the water bath temperature is 50-60 ℃, and the distillation is stopped when the ratio of the weight of the residual liquid after the concentration to the weight of the 5-hydroxytryptamine hydrochloride added is 3-3.5: 1.

Technical Field

The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a method for synthesizing 5-hydroxytryptamine adipate.

Background

5-Hydroxytryptamine adipate was a white powdery solid with melting point 177-. It is used for treating cardiovascular failure of IHD patients and heart surgery patients, improving contractile activity of low-power region of cardiac muscle, and recovering functions of surgery and treating impaired smooth muscle function of patients. 5-hydroxytryptamine adipate bound to serotonin receptors of visceral smooth muscle, normalizing its contractile activity. The demand of 5-hydroxytryptamine adipate on the market is large due to the excellent performance of the 5-hydroxytryptamine adipate, but the current technology for synthesizing the 5-hydroxytryptamine adipate is blank and cannot realize industrial production, so that the synthesis method which is mild in reaction condition and easy for industrial production is provided.

Disclosure of Invention

The invention provides a method for synthesizing 5-hydroxytryptamine adipate, which saves cost, is easy for industrial production, and solves the problem that the prior art cannot synthesize the 5-hydroxytryptamine adipate.

The reaction route of the invention is as follows:

the technical scheme of the invention is as follows:

a method of synthesizing 5-hydroxytryptamine adipate comprising the steps of:

s1, stirring and dissolving the 5-hydroxytryptamine hydrochloride and the organic alcohol aqueous solution;

s2, dropwise adding a sodium hydroxide solution until the pH value is 8 +/-0.5, and continuously stirring;

s3, controlling the temperature, dropwise adding adipic acid, and continuously stirring;

and S4, post-processing.

As a further technical scheme, the mass concentration of the organic alcohol aqueous solution is 40% -50%, the weight ratio of the organic alcohol aqueous solution to 5-hydroxytryptamine hydrochloride is 8:1-10:1, and the organic alcohol aqueous solution is one of an ethanol aqueous solution, a methanol aqueous solution and an isopropanol aqueous solution.

As a further technical scheme, the organic alcohol aqueous solution is an ethanol aqueous solution.

As a further technical scheme, the stirring time in the step S1 is 5-10 min.

As a further technical scheme, the concentration of the sodium hydroxide solution in the step S2 is 10% -15%.

As a further technical scheme, the stirring is continued for 30-40h in the step S2.

As a further technical scheme, the temperature is controlled to be 20-30 ℃ during the dropwise adding and the continuous stirring in the step S2.

As a further technical scheme, in the step S3, the molar ratio of adipic acid to 5-hydroxytryptamine hydrochloride is 1.1:1-1.2: 1.

As a further technical proposal, in the step S3, the temperature is controlled to be 15-25 ℃.

As a further technical scheme, in the step S3, the dripping time is controlled to be 20-30 min.

As a further technical proposal, in the step S3, the continuous stirring time is 30-35 min.

As a further technical scheme, the step S4 is specifically vacuum distillation, temperature reduction, stirring, suction filtration, washing and drying.

As a further technical scheme, in the step S4, the specific conditions of the reduced pressure distillation are as follows: under the vacuum of-0.09 to-0.095 MPa, the water bath temperature is 50 to 60 ℃, the ratio of the weight of the residual liquid to be concentrated after distillation to the weight of the 5-hydroxytryptamine hydrochloride added is 3 to 3.5:1 hour, the distillation was stopped.

As a further technical scheme, in the step S4, the temperature is reduced to 10-15 ℃, and the stirring is continued for 0.5 h.

As a further technical scheme, in the step S4, deionized water which is 3-3.5 times of the weight of the 5-hydroxytryptamine hydrochloride is added during washing.

The invention has the beneficial effects that:

1. the invention provides a method for synthesizing 5-hydroxytryptamine adipate, which has the advantages of simple synthesis process, mild synthesis process conditions, high yield of over 85.5 percent, good quality and content of more than 99.5 percent. The method for synthesizing the 5-hydroxytryptamine adipate provided by the invention saves the cost, has mild process conditions, and is easy for industrial production.

2. In the invention, the organic alcohol aqueous solution is adopted, and hydrochloric acid is removed by using the sodium hydroxide solution to obtain a homogeneous solution, and if other solutions or pure water is adopted, emulsion is generated to influence the subsequent reaction.

3. In the experimental process, the inventor finds that in the process of synthesizing the 5-hydroxytryptamine adipate, the molar ratio of the 5-hydroxytryptamine hydrochloride to the adipic acid needs to be controlled to be 1:1.1-1.2, when the molar ratio is more than 1.2, the product purity is low, residual adipic acid is low, and when the molar ratio is less than 1.1, the product purity is low, and the by-product di- (5-hydroxytryptamine) adipate is contained. Based on the molar ratio, the reaction temperature and the reaction time must be controlled, the side reaction is generated when the temperature is too high or the reaction time is too long, the temperature is too low or the reaction time is too short, the reaction of adipic acid is incomplete, and the product quality is poor.

Drawings

The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.

FIG. 1 is a high pressure liquid phase spectrum of 5-hydroxytryptamine adipate prepared in example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.

Example 1

Adding 175g of 50% ethanol aqueous solution into a 500ml three-neck bottle, then adding 21.25g of 5-hydroxytryptamine hydrochloride into the ethanol solution, stirring and dispersing for 5min, then dripping 10% sodium hydroxide solution into the ethanol solution, controlling the temperature at 20-25 ℃ until the pH value of the solution system is 8, and then keeping the pH value at 20-25 ℃ and stirring for 10 min. Then weighing 16.07g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system at 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 0.5h after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 74 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

Filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 64g of deionized water for washing, draining to obtain a 5-hydroxytryptamine adipate solid wet product, and drying to obtain 27.76g of white-like 5-hydroxytryptamine adipate solid, wherein the molar yield is 86.0% and the liquid phase content is 99.75%.

Example 2

Adding 210g of 50% ethanol aqueous solution into a 500ml three-neck flask, then adding 21.25g of 5-hydroxytryptamine hydrochloride into the ethanol solution, stirring and dispersing for 5min, then dripping 10% sodium hydroxide solution into the ethanol solution, controlling the temperature at 25-30 ℃ until the pH value of the solution system is 8, and then keeping the pH value at 25-30 ℃ and stirring for 10 min. Then weighing 17.53g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system at 20-25 ℃ in the adding process, adding for 30min, and continuing stirring for 0.5h after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 64 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

And filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 74g of deionized water for washing, draining to obtain a wet 5-hydroxytryptamine adipate solid product, and drying to obtain 28.77g of white-like 5-hydroxytryptamine adipate solid, wherein the molar yield of the product is 89.0% and the liquid phase content is 99.61%.

Example 3

In a 500ml three-necked flask, 175g of 50% isopropanol aqueous solution is added, then 21.25g of 5-hydroxytryptamine hydrochloride is added to the ethanol solution, the mixture is stirred and dispersed for 5min, then 10% sodium hydroxide solution is dripped into the ethanol solution, the temperature is controlled between 20 ℃ and 25 ℃ until the pH value of the solution system is 8, and then the solution system is kept at the pH value of 8 at the temperature between 20 ℃ and 25 ℃ and stirred for 10 min. Then weighing 16.81g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system to be 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 25 min after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 70 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

And filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 65g of deionized water for washing, draining to obtain a 5-hydroxytryptamine adipate solid wet product, and drying to obtain 27.94g of white-like 5-hydroxytryptamine adipate solid, wherein the molar yield is 84.8% and the liquid phase content is 97.73%.

Comparative example 1

In a 500ml three-necked bottle, 175g of 50% ethanol water is added, then 21.25g of 5-hydroxytryptamine hydrochloride is added to the ethanol solution, the mixture is stirred and dispersed for 5min, then 10% sodium hydroxide solution is dripped into the ethanol solution, the temperature is controlled to be 20-25 ℃ until the pH value of the solution system is 8, and then the solution system is kept at 20-25 ℃ and stirred for 10 min. Then weighing 15.48g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system to be 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 0.5h after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 74 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

Filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 64g of deionized water for washing, draining to obtain a 5-hydroxytryptamine adipate solid wet product, and drying to obtain 27.49g of white-like 5-hydroxytryptamine adipate solid, wherein the molar yield is 83.5% and the liquid phase content is 97.82%.

Comparative example 2

In a 500ml three-necked bottle, 175g of 50% ethanol water is added, then 21.25g of 5-hydroxytryptamine hydrochloride is added to the ethanol solution, the mixture is stirred and dispersed for 5min, then 10% sodium hydroxide solution is dripped into the ethanol solution, the temperature is controlled to be 20-25 ℃ until the pH value of the solution system is 8, and then the solution system is kept at 20-25 ℃ and stirred for 10 min. Then weighing 18.43g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system to be 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 0.5h after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 74 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

And filtering the materials in the bottle by using a filter flask to obtain a white-like solid, after the filtrate is drained, adding 64g of deionized water for washing, draining to obtain a wet 5-hydroxytryptamine adipate solid product, and drying to obtain 28.04g of white-like 5-hydroxytryptamine adipate solid, wherein the yield is 85.8 percent, and the content is 98.52 percent.

Comparative example 3

In a 500ml three-necked bottle, 175g of 50% ethanol water is added, then 21.25g of 5-hydroxytryptamine hydrochloride is added to the ethanol solution, the mixture is stirred and dispersed for 5min, then 10% sodium hydroxide solution is dripped into the ethanol solution, the temperature is controlled to be 20-25 ℃ until the pH value of the solution system is 8, and then the solution system is kept at 20-25 ℃ and stirred for 10 min. Then weighing 16.07g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system at 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 40 min after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 74 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

Filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 64g of deionized water for washing, draining to obtain a 5-hydroxytryptamine adipate solid wet product, and drying to obtain 27.98g of white-like 5-hydroxytryptamine adipate solid, wherein the yield is 85.96%, and the content is 98.92%.

Comparative example 4

In a 500ml three-necked bottle, 175g of 50% ethanol water is added, then 21.25g of 5-hydroxytryptamine hydrochloride is added to the ethanol solution, the mixture is stirred and dispersed for 5min, then 10% sodium hydroxide solution is dripped into the ethanol solution, the temperature is controlled to be 20-25 ℃ until the pH value of the solution system is 8, and then the solution system is kept at 20-25 ℃ and stirred for 10 min. Then weighing 16.07g of adipic acid solid, slowly adding into the solution, controlling the temperature of the temperature system at 15-20 ℃ in the adding process, adding for 20min, and continuing stirring for 25 min after the adding is finished.

And transferring the reacted solution into a rotary evaporator, opening a vacuum system, starting a heating device, controlling the water bath temperature to be 50-60 ℃ under the vacuum of-0.09 to-0.095 MPa, distilling the ethanol water solution under reduced pressure, and stopping distillation when the weight of the concentrated residual liquid is 74 g. Switching ice water bath to cool to 10-15 ℃, and continuing stirring for 0.5 h.

Filtering the materials in the bottle by a filter flask to obtain a white-like solid, after the filtrate is drained, adding 64g of deionized water for washing, draining to obtain a 5-hydroxytryptamine adipate solid wet product, and drying to obtain 27.77g of white-like 5-hydroxytryptamine adipate solid, wherein the yield is 85.16%, and the content is 98.73%.

The products obtained in the examples 1 and 2 have the yield of over 86 percent, the liquid phase content of more than 99.5 percent, mild reaction conditions and suitability for industrial production, and the adipic acid is added in a large amount or a small amount in the comparative examples 1 and 2, so that the product purity is reduced and the yield is reduced. In comparative examples 3 and 4, the purity of 5-hydroxytryptamine adipate obtained by prolonging or shortening the reaction time based on example 1 was lower than that of the examples.

The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.