阅读说明：本技术 一种一锅法合成香豆酰多巴胺的方法 (Method for synthesizing coumaroyl dopamine by one-pot method ) 是由 徐骏 史海龙 黄斌 张正阳 于 2021-09-13 设计创作，主要内容包括：本发明公开了一种一锅法合成香豆酰多巴胺的方法,所述方法包括如下步骤：(1)以香豆酸为原料,在三乙胺作用下,与氯甲酸乙酯反应,得到中间体III；(2)中间体III与盐酸多巴胺在三乙胺作用下,发生缩合,得到中间体V；(3)中间体V用水合肼处理,得到目标化合物I,即所述香豆酰多巴胺。本发明方法具有高效高收率的优点,且适合大规模工业化生产。(The invention discloses a method for synthesizing coumaroyl dopamine by a one-pot method, which comprises the following steps: (1) reacting coumaric acid serving as a raw material with ethyl chloroformate under the action of triethylamine to obtain an intermediate III; (2) condensing the intermediate III and dopamine hydrochloride under the action of triethylamine to obtain an intermediate V; (3) and (3) treating the intermediate V with hydrazine hydrate to obtain a target compound I, namely the coumaroyl dopamine. The method has the advantages of high efficiency and high yield, and is suitable for large-scale industrial production.)

1. A method for synthesizing coumaroyl dopamine by a one-pot method is characterized by comprising the following steps:

(1) reacting coumaric acid serving as a raw material with ethyl chloroformate under the action of triethylamine to obtain an intermediate III;

(2) condensing the intermediate III and dopamine hydrochloride under the action of triethylamine to obtain an intermediate V;

(3) and (3) treating the intermediate V with hydrazine hydrate to obtain a target compound I, namely the coumaroyl dopamine.

2. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (1), the molar ratio of coumaric acid, ethyl chloroformate and triethylamine is 1:2.1-2.3: 2.3-2.5.

3. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (1), the reaction solvent is dichloromethane, and the volume amount of the reaction solvent is 5-8 times that of coumaric acid.

4. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (1), the reaction temperature is 0-10 ℃ and the reaction time is 1-2 h.

5. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (2), the molar ratio of coumaric acid, dopamine hydrochloride and triethylamine is 1:1-1.2: 1.1-1.3.

6. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (2), the reaction solvent is dimethylformamide and the volume amount of the dimethylformamide is 1.5-2.5 times of that of dopamine hydrochloride.

7. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (2), the reaction temperature is 0-10 ℃ and the reaction time is 1-2 h.

8. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (3), the mass concentration of hydrazine hydrate is 80%, and the molar ratio of coumaric acid to hydrazine hydrate is 1: 1.5-2.

9. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (3), the molar ratio of coumaric acid to hydrazine hydrate is 1: 1.7.

10. The one-pot method for synthesizing coumaroyl dopamine according to claim 1, wherein in the step (3), the reaction temperature is room temperature, and the reaction time is 2-4 h.

Technical Field

The invention relates to the field of organic synthesis, in particular to a method for synthesizing coumaroyl dopamine by a one-pot method.

Background

Coumaroyldopamine has an inhibitory effect on the synthesis of prostaglandins and leukotrienes in vitro and exhibits a certain antioxidant effect, and thus has been widely studied. The main synthetic methods reported so far are roughly as follows: 1, the coumaric acid and the dopamine are directly used for condensation reaction under the action of a condensing agent, but as the coumaric acid and the dopamine have one or more phenolic hydroxyl groups on molecular structures and can participate in the condensation reaction more or less, the product is complex, the number of byproducts is large, the purification is difficult, the yield is not high, and the amplification production is not facilitated. 2, the phenolic hydroxyl in the molecular structures of coumaric acid and dopamine is protected and then condensed, the synthesis strategy solves the problem of more direct condensation byproducts, but the protective group is not easy to remove no matter the protective group is an alkyl protective group or a silane protective group, or the protective group is unstable in the reaction process.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a one-pot synthesis method of coumaroyl dopamine, which is high in efficiency, high in yield and suitable for large-scale industrial production.

The technical scheme adopted by the invention is as follows:

a method for synthesizing coumaroyl dopamine by a one-pot method is carried out according to the following synthetic route:

(1) reacting coumaric acid serving as a raw material with ethyl chloroformate under the action of triethylamine to obtain an intermediate III;

(2) condensing the intermediate III and dopamine hydrochloride under the action of triethylamine to obtain an intermediate V;

(3) and (3) treating the intermediate V with hydrazine hydrate to obtain a target compound I, namely the coumaroyl dopamine.

In the step (1), the mol ratio of coumaric acid, ethyl chloroformate and triethylamine is 1:2.1-2.3: 2.3-2.5; preferably, the molar ratio of coumaric acid, ethyl chloroformate and triethylamine is 1:2.2: 2.4.

In the step (1), the reaction solvent is dichloromethane, and the volume consumption is 5-8 times, preferably 6 times of that of coumaric acid.

In the step (1), the reaction temperature is 0-10 ℃, and the reaction time is 1-2 h; preferably 5 ℃ for 1 h.

In the step (2), the molar ratio of coumaric acid to dopamine hydrochloride to triethylamine is 1:1-1.2: 1.1-1.3.

Preferably, the molar ratio of coumaric acid to dopamine hydrochloride to triethylamine is 1:1.1: 1.2.

In the step (2), the reaction solvent is dimethylformamide, and the volume consumption of the dimethylformamide is 1.5-2.5 times, preferably 2 times of that of dopamine hydrochloride.

In the step (2), the reaction temperature is 0-10 ℃, and the reaction time is 1-2 h; preferably 5 ℃ for 1 h.

In the step (3), the mass concentration of hydrazine hydrate is 80%, and the molar ratio of coumaric acid to hydrazine hydrate is 1: 1.5-2.

In the step (3), the molar ratio of coumaric acid to hydrazine hydrate is 1: 1.7.

In the step (3), the reaction temperature is room temperature, and the reaction time is 2-4 h. Preferably, the reaction is carried out at 25 ℃ for 2 h.

The beneficial technical effects of the invention are as follows:

the method provided by the invention provides a synthetic method which is simple to operate, economic and efficient and can be used for large-scale production for coumaroyl dopamine, and two intermediates do not need to be purified separately and directly enter the next step of reaction in a reaction system until the final product is obtained. The introduction of the carbonic ester protects the naked phenolic hydroxyl group on one hand and avoids participating in the subsequent condensation reaction, and on the other hand, the carbonic ester and the carboxylic acid form mixed anhydride, thereby avoiding the use of other expensive condensation reagents which are difficult to purify. In the condensation stage, the target structure is a dominant product by controlling the temperature and the dosage of alkali and utilizing the activity difference of aliphatic amino and phenolic hydroxyl. This method has been applied to scale-up production.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of coumaroyl dopamine prepared in example 1 of the present invention.

Detailed Description

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

Example 1:

a method for synthesizing coumaroyl dopamine by a one-pot method comprises the following specific steps:

(1): 240L of dichloromethane, 40kg of coumaric acid (244mol) and 58.2kg of ethyl chloroformate (536mol) are added into a reaction kettle, stirring is started, the temperature is reduced to 5 ℃, 59.1kg of triethylamine (585mol) is added dropwise, the reaction is continued for 1 hour, 160L of 3% sodium bicarbonate aqueous solution is added for washing, and a dichloromethane layer is separated and is directly used for the next reaction.

(2): adding 102L of dimethylformamide, 50.9kg of dopamine hydrochloride (268mol) and 29.6kg of triethylamine (293mol) into a reaction kettle, starting stirring, cooling to 5 ℃, dropwise adding the dichloromethane solution in the previous step, continuing to react for 1 hour, adding 160L of water, adjusting the pH value to 3-4 by using concentrated hydrochloric acid, separating an organic phase, washing twice by using 160L of saturated saline solution, and evaporating the solvent for the next step of reaction.

(3): adding 26L of hydrazine hydrate (416mol) and 78L of water into the reaction kettle, stirring at room temperature for 2 hours, filtering solids, washing the solids with 0.5mol/L dilute hydrochloric acid and water, and drying to obtain 48kg of target product.

The nmr spectrum of the obtained product is shown in fig. 1, and it can be seen from fig. 1 that three monohydrogen peaks with chemical shifts of 9.85ppm, 8.78ppm and 8.67ppm respectively correspond to three phenolic hydroxyl hydrogens, a monohydrogen triplet with a small coupling constant at a chemical shift of 8.02ppm corresponds to a nitrogen hydrogen of an amide bond, two groups of a dihydrogen doublet with chemical shifts of 7.38ppm and 6.79ppm respectively correspond to two groups of aromatic hydrogens of the same chemical environment on the benzene ring of the coumaric acid segment, two monohydrogen doublets with a large coupling constant at a chemical shift of 7.31ppm and 6.40ppm correspond to two alkene hydrogens on the coumaric acid segment, a monohydrogen doublet with a chemical shift of 6.64ppm, a monohydrogen doublet with a chemical shift of 6.60ppm (meta remote coupling), a monohydrogen quartet with a chemical shift of 6.46ppm (meta remote coupling) corresponds to three aromatic hydrogens on the benzene ring of the dopamine segment, and two groups of a dihydrogen multiplets with chemical shifts of 3.32ppm and 2.55ppm correspond to two adjacent methylene multiplets of the dopamine segment.

Example 2:

a method for synthesizing coumaroyl dopamine by a one-pot method comprises the following specific steps:

(1): 320mL of dichloromethane, 40g of coumaric acid (0.244mol) and 60.9g of ethyl chloroformate (0.561mol) are added into a reaction bottle, stirring is started, the temperature is reduced to 10 ℃, 61.6g of triethylamine (0.61mol) is added dropwise, the reaction is continued for 2 hours, 160mL of 3% sodium bicarbonate aqueous solution is added for washing, and a dichloromethane layer is separated and is directly used for the next reaction.

(2): 139mL of dimethylformamide, 55.5g of dopamine hydrochloride (0.268mol) and 32g of triethylamine (0.317mol) are added into a reaction bottle, stirring is started, the temperature is reduced to 10 ℃, the dichloromethane solution in the previous step is dropwise added, the reaction is continued for 2 hours, 160mL of water is added, the pH value is adjusted to 3-4 by concentrated hydrochloric acid, an organic phase is separated, the organic phase is washed twice by 160mL of saturated saline solution, and the solvent is evaporated for the next step of reaction.

(3): 30.5mL of hydrazine hydrate (0.488mol) and 78mL of water are added into the reaction bottle, the mixture is stirred for 2 hours at room temperature, the solid is filtered, the solid is washed by 0.5mol/L dilute hydrochloric acid and water, and 42g of target product is obtained after drying.

Example 3:

a method for synthesizing coumaroyl dopamine by a one-pot method comprises the following specific steps:

(1): 200mL of dichloromethane, 40g of coumaric acid (0.244mol) and 55.6g of ethyl chloroformate (0.512mol) are added into a reaction bottle, stirring is started, the temperature is reduced to 0 ℃, 56.7g of triethylamine (0.561mol) is added dropwise, the reaction is continued for 1 hour, 160mL of 3% sodium bicarbonate aqueous solution is added for washing, and a dichloromethane layer is separated and is directly used for the next reaction.

(2): 69.5mL of dimethylformamide, 46.3g of dopamine hydrochloride (0.244mol) and 27.1g of triethylamine (0.268mol) are added into a reaction bottle, stirring is started, the temperature is reduced to 0 ℃, the dichloromethane solution in the previous step is dropwise added, the reaction is continued for 1 hour, 160mL of water is added, the pH value is adjusted to 3-4 by concentrated hydrochloric acid, an organic phase is separated out, the organic phase is washed twice by 160mL of saturated saline solution, and the solvent is evaporated and used for the next step of reaction.

(3): 22.9mL of hydrazine hydrate (0.366mol) and 78mL of water are added into the reaction bottle, stirred for 4 hours at room temperature, the solid is filtered, and the solid is washed by 0.5mol/L diluted hydrochloric acid and water and dried to obtain 43g of the target product.