Preparation method of (+ / -)-noradrenaline

Abstract

The invention provides a preparation method of (+ / -)-noradrenaline. Comprising the following steps: (a) adding 1-(3, 4-dihydroxyphenyl)-2-aminoethanone and Bronsted acid into a polar protic solvent, and heating to dissolve the 1-(3, 4-dihydroxyphenyl)-2-aminoethanone and the Bronsted acid; (b) transferring the solution obtained in the step (a) into a hydrogenation bottle, firstly adding palladium / carbon, then replacing gas in the bottle, hydrogenating to 3-5 atmospheric pressures, controlling the internal temperature to be 35-50 DEG C, and keeping for 2-5 hours; and (c) after the reaction is finished, filtering, cooling the filtrate, dropwise adding ammonia water until the pH value of the reaction liquid is 9-10, filtering the separated solid, and drying to obtain the (+ / -)-noradrenaline. According to the invention, an intermediate 1-(3, 4-dihydroxyphenyl)-2-aminoethanone obtained by substitution and hydrolysis of chloroacetyl catechol is used as a raw material, and (+ / -)-noradrenaline is prepared by hydrogenation in a specific polar protic solvent through Bronsted acid activation and palladium-carbon catalysis. The technological process is simple and convenient, the reaction condition is mild, the reaction is rapid, the requirement for equipment is low, and the obtained product is high in yield, high in purity, few in by-product and especially suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a preparation method of (±)-norepinephrine. BACKGROUND

[0002] Norepinephrine, the scientific name of which is 1-(3,4-dihydroxyphenyl)-2-aminoethanol, is a neurotransmitter in the human body and a commonly used hormone in clinical practice. In medicine, it is mainly used for treating hypotension, shock or hypotension caused by acute myocardial infarction, extracorporeal circulation, resection of pheochromocytoma, and blood volume deficiency.

[0003]

[0004] Norepinephrine is a catecholamine compound in chemistry. The traditional preparation process includes the following steps: first, o-diphenol and chloroacetyl chloride undergo Friedel-Crafts acylation reaction under the action of aluminum chloride to obtain chloroacetyl catechol. Second, the product is subjected to aminolysis with ammonia or a Delbin reaction with urotropine to obtain an aminated intermediate. Third, the aminated intermediate is subjected to palladium-carbon catalytic hydrogenation to obtain racemic norepinephrine. Fourth, the obtained racemate is subjected to resolution to finally obtain R-norepinephrine with pharmaceutical activity.

[0005] After years of research, the existing preparation technology of norepinephrine mainly focuses on its chemical structure. Specifically, norepinephrine is a catecholamine compound in chemistry. The traditional preparation process includes the following steps: first, o-diphenol and chloroacetyl chloride undergo Friedel-Crafts acylation reaction under the action of aluminum chloride to obtain chloroacetyl catechol. Second, the product is subjected to aminolysis with ammonia or a Delbin reaction with urotropine to obtain an aminated intermediate. Third, the aminated intermediate is subjected to palladium-carbon catalytic hydrogenation to obtain racemic norepinephrine. Fourth, the obtained racemate is subjected to resolution to finally obtain R-norepinephrine with pharmaceutical activity.

[0006] Chinese patents CN112079733A and CN108069863B report a method for asymmetric synthesis of norepinephrine. Chiral catalysts such as chiral oxazoles borane or alpha-pinene borane are used in asymmetric reduction, and special CBS reduction system is used in the reduction condition, which has high cost, complex reaction, and complicated post-treatment process, and is not suitable for industrial production. Diastereomeric salt crystallization is simple, efficient, and relatively low in cost, and is more easily transferred to production scale-up, and is more selected and applied in industry. Therefore, optimizing the catalytic hydrogenation of the aminated intermediate is also an important link for improving the quality of norepinephrine.

[0007] In summary, how to design a preparation method of (±)-norepinephrine with simple process, mild reaction, high yield and high purity is a problem to be solved by those skilled in the art. SUMMARY

[0008] The present application aims to provide a preparation method of (±)-norepinephrine, which uses chloroacetyl catechol (molecular formula: C8H7ClO3, CAS No. 99-40-1) to replace the hydrolyzed intermediate 1-(3,4-dihydroxyphenyl)-2-aminoethanone (molecular formula: C8H9NO3, CAS No. 499-61-6) as raw material, and is prepared by Bronsted acid activation, palladium / carbon catalysis and hydrogenation in a specific polar protic solvent.

[0009] In the present application, the problem of solubility of the raw material is effectively solved by introducing Bronsted acid activation, and a small amount of Bronsted acid can achieve good reaction effect, and the salt of the acid and the free amine in the product prevents the poisoning of the palladium / carbon catalyst. In addition, the solubility of the raw material in the reaction system is further improved by the specific composition of the polar protic solvent, the reaction rate is accelerated, the side reaction is reduced, and the purity of the product is improved.

[0010] To achieve the above-mentioned purpose, the present application provides a preparation method of (±)-norepinephrine, which specifically comprises the following steps:

[0011] (a) adding 1-(3,4-dihydroxyphenyl)-2-aminoethanone and Bronsted acid in a polar protic solvent, and dissolving at a temperature of 35-50°C;

[0012] (b) moving the solution obtained in step (a) into a hydrogenation bottle, first adding palladium / carbon, then replacing the gas in the bottle, and then adding hydrogen to 3-5 atm, controlling the internal temperature at 35-50°C for 2-5 h;

[0013] (c) after the reaction is completed, filtering, and then adding ammonia water to the filtrate until the pH of the reaction solution is 9-10, and then filtering and drying the precipitated solid to obtain (±)-norepinephrine.

[0014] In a preferred embodiment, in step (a), the polar protic solvent is composed of water and an organic solvent in a mass ratio of (1-3):1, wherein the organic solvent is one or more of methanol, ethanol, trifluoroethanol and N,N-dimethylformamide; preferably, the polar protic solvent is composed of water and an organic solvent in a mass ratio of 2:1.

[0015] In a preferred embodiment, in step (a), the mass ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethanone to the polar protic solvent is 1:(3-6); preferably, the mass ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethanone to the polar protic solvent is 1:4.

[0016] In a preferred embodiment, in step (a), the Bronsted acid comprises one or more of tartaric acid, salicylic acid, benzoic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and methanesulfonic acid.

[0017] In a preferred embodiment, in step (a), the molar ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethanone to Bronsted acid is 1:(0.1-0.4); preferably, the molar ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethanone to Bronsted acid is 1:0.2.

[0018] In a preferred embodiment, in step (b), the palladium content of the palladium / carbon is 10%, and the water is 50%; the mass ratio of the palladium / carbon to 1-(3,4-dihydroxyphenyl)-2-aminoethanone in step (a) is (0.036-0.073):1; preferably, the mass ratio of the palladium / carbon to 1-(3,4-dihydroxyphenyl)-2-aminoethanone in step (a) is 0.048:1.

[0019] In a preferred embodiment, in step (b), the gas used for the replacement is nitrogen, and the replacement is performed 2-3 times.

[0020] In a preferred embodiment, in step (c), the filtrate is cooled to 0-5°C; preferably, the filtrate is cooled to 1-4°C.

[0021] In a preferred embodiment, in step (c), the mass fraction of the ammonia water is 22-25%.

[0022] In a preferred embodiment, in step (c), the drying can be performed by using a conventional method known to those skilled in the art, such as vacuum drying at 35-45°C for 5-10 hours.

[0023] In a preferred embodiment, in step (c), the yield of the obtained (±)-norepinephrine is above 94.1%, and the purity of the obtained (±)-norepinephrine is above 99.7%.

[0024] Compared with the prior art, the technical scheme of the present application has the following advantages:

[0025] 1. In the present application, the problem of solubility of raw materials is effectively solved by introducing Bronsted acid activation, and good reaction results can be achieved with a small amount of Bronsted acid; at the same time, the salt of the acid and the free amine in the product prevents the poisoning of the palladium / carbon catalyst.

[0026] 2. In the present application, the solubility of raw materials in the reaction system is further improved by using a polar protic solvent with a specific composition, the reaction rate is accelerated, the side reactions are reduced, and the purity of the product is improved.

[0027] 3. When the salt of (±)-norepinephrine is free from base in the present application, only a small amount of ammonia water is needed to neutralize, so that the required pH value can be reached, avoiding the use of too much concentrated ammonia water which is a highly polluting raw material, effectively reducing the discharge of three wastes, saving energy and reducing consumption, increasing efficiency, and more suitable for industrial production.

[0028] 4. The preparation method provided by the present application has simple process, mild reaction conditions, rapid reaction, low equipment requirements, high product yield, high purity, and few by-products, and has broad application prospects. DETAILED DESCRIPTION

[0029] In order to make those skilled in the art better understand the present application, the present application will be further described in detail below in combination with specific embodiments, but it should be understood that the protection scope of the present application is not limited by the specific embodiments. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0030] Unless otherwise specified, the technical means used in the present application are conventional means known to those skilled in the art, and various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or can be prepared by existing methods. The reagents used in the present application are analytical pure unless otherwise specified.

[0031] Example 1

[0032] In a flask, 100 g of 1-(3,4-dihydroxyphenyl)-2-aminoethanone, 133 g of methanol, 266 g of water, and 14.6 g of benzoic acid were added, and heated to 45℃ under stirring, then transferred to a 1L hydrogenation flask, 4.8 g of 10% palladium on carbon (Pd10%; water 50%) was added, replaced with nitrogen for 2 times and hydrogenated to 3 atmospheres, the internal temperature was controlled at 45℃ for 3h, and then filtered. The filtrate was cooled to 3℃, 23% concentrated ammonia water was added, the pH value was adjusted to 9, filtered, and vacuum dried to constant weight to obtain 95.2 g of solid, with a yield of 94.1% and a purity of 99.8% detected by HPLC.

[0033] Example 2

[0034] In a flask, add 1-(3,4-dihydroxyphenyl)-2-aminoethanone 100 g, methanol 133 g, water 266 g, methyl sulfonic acid 11.5 g, heat to 45 °C under stirring, transfer to a 1 L hydrogenation flask, add 10% palladium on carbon (Pd 10%; water 50%) 4.8 g, replace with nitrogen for 2 times and hydrogenate to 3 atm, control the internal temperature at 45 °C for 3 h, filter. Cool the filtrate to 3 °C, add concentrated ammonia with 23% mass fraction, adjust the pH value to 9, filter, vacuum dry to constant weight, obtain solid 96.5 g, yield 95.3%, purity 99.7% by HPLC.

[0035] Comparative Example 1

[0036] In a flask, add 1-(3,4-dihydroxyphenyl)-2-aminoethanone 100 g, methanol 133 g, water 266 g, hydrochloric acid 12.1 g, heat to 45 °C under stirring, transfer to a 1 L hydrogenation flask, add 10% palladium on carbon (Pd 10%; water 50%) 4.8 g, replace with nitrogen for 2 times and hydrogenate to 3 atm, control the internal temperature at 45 °C for 6 h, filter. Cool the filtrate to 3 °C, add concentrated ammonia with 23% mass fraction, adjust the pH value to 9, filter, vacuum dry to constant weight, obtain solid 91.2 g, yield 90.1%, purity 99.3% by HPLC.

[0037] Comparative Example 2

[0038] In a flask, add 1-(3,4-dihydroxyphenyl)-2-aminoethanone 100 g, water 400 g, benzoic acid 14.6 g, heat to 45 °C under stirring, transfer to a 1 L hydrogenation flask, add 10% palladium on carbon (Pd 10%; water 50%) 4.8 g, replace with nitrogen for 2 times and hydrogenate to 3 atm, control the internal temperature at 45 °C for 15 h, filter. Cool the filtrate to 3 °C, add concentrated ammonia with 23% mass fraction, adjust the pH value to 9, filter, vacuum dry to constant weight, obtain solid 93.9 g, yield 92.8%, purity 98.9% by HPLC.

[0039] The foregoing description of specific exemplary embodiments of the application will be better understood when read in conjunction with the accompanying drawings. It should be understood that the description is illustrative but not restrictive; many variations and modifications are possible. The exemplary embodiments were chosen and described in order to explain the principles of the application and its practical application, thereby enabling others skilled in the art to understand the application for various embodiments and with various modifications as are suited to the particular use contemplated. The scope of the application is defined by the claims and their equivalents.

Claims

1. A method for preparing (±)-norepinephrine, characterized in that, Includes the following steps: (a) Add 1-(3,4-dihydroxyphenyl)-2-aminoethyl ketone and Bronsted acid to a polar protic solvent and heat to 35-50°C to dissolve; (b) Transfer the solution obtained in step (a) into a hydrogenation flask, add palladium / carbon first, then replace the gas in the flask, add hydrogen to 3-5 atmospheres, and maintain the internal temperature at 35-50℃ for 2-5 hours; (c) After the reaction is complete, filter the solution. After the filtrate is cooled to a certain temperature, add ammonia dropwise until the pH of the reaction solution is 9-10. Filter the precipitated solid and dry it to obtain (±)-norepinephrine.

2. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (a), the polar protic solvent is composed of water and an organic solvent in a mass ratio of (1-3):1, wherein the organic solvent is one or more of methanol, ethanol, trifluoroethanol, and N,N-dimethylformamide.

3. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (a), the mass ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethyl ketone to the polar protic solvent is 1:(3-6).

4. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (a), the Bronsted acid includes one or more of tartaric acid, salicylic acid, benzoic acid, p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, trifluoromethanesulfonic acid, and methanesulfonic acid.

5. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (a), the molar ratio of 1-(3,4-dihydroxyphenyl)-2-aminoethyl ketone to Bronsted acid is 1:(0.1-0.4).

6. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (b), the palladium content in the palladium / carbon is 10%; The mass ratio of palladium / carbon to 1-(3,4-dihydroxyphenyl)-2-aminoethyl ketone in step (a) is (0.036-0.073):

1.

7. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (b), the gas used for the replacement is nitrogen, and the replacement is performed 2-3 times.

8. The method for preparing (±)-norepinephrine as described in claim 1, characterized in that, In step (c), the filtrate is cooled to 0-5°C.

9. The method for preparing (±)-norepinephrine according to any one of claims 1-8, characterized in that, In step (c), the yield of (±)-norepinephrine obtained is above 94.1%, and the purity of (±)-norepinephrine obtained is above 99.7%.

Images