Preparation method of norepinephrine bitartrate

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of norepinephrine bitartrate. The preparation method of noradrenaline bitartrate comprises the following steps: carrying out condensation reaction on catechol and N-benzyl glycine in a solvent under the action of an activating agent to obtain N-benzyl noradrenaline ketone hydrochloride; catalytic hydrogenation and deprotection are carried out, such that racemic noradrenaline is obtained through conversion; reacting with L-tartaric acid; wherein the activating agent is at least one of trifluoroacetic anhydride and dichloro dicyanobenzoquinone. Compared with the prior art, the method has the advantages that the yield of the N-benzyl norepinephrine ketone hydrochloride is obviously improved, the process operation is simple and convenient, the product purity is high, and a new technical scheme is provided for efficient industrial production of norepinephrine bitartrate.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing norepinephrine bitartrate. Background Art

[0002] Norepinephrine bitartrate is an important drug commonly used in clinical practice, mainly used to treat acute hypotension, cardiogenic shock and other symptoms of unstable blood circulation caused by various reasons. Its chemical structure contains chiral centers, so the purity of intermediates and the yield of target products are required to be high during the preparation process. However, the synthesis of this drug usually requires multiple complex steps, including the condensation reaction of catechol and nitrogen-containing compounds, catalytic hydrogenation deprotection and subsequent chiral resolution steps. Each step involves high technical requirements and is accompanied by large material consumption and by-product generation. These problems lead to low efficiency of the current synthesis route and difficulty in improving product yield. In addition, the activators and catalysts used in the prior art are often highly toxic and corrosive, which not only increases the difficulty of operation and equipment maintenance costs, but also puts great pressure on the environment. These factors significantly limit the industrial production capacity of norepinephrine bitartrate.

[0003] In Chinese invention patent CN115073312A, a method for synthesizing noradrenaline bitartrate using chloroacetic acid and catechol as starting materials is disclosed. The method generates a key intermediate N-benzyl noradrenaline ketone hydrochloride by a condensation reaction of chloroacetic acid and catechol, and then prepares the final product by catalytic hydrogenation and chiral resolution steps. Although the technology has certain improvements in reaction control and process implementation, it still has obvious limitations, especially in the selection of activators. The activators used in the existing scheme have limited promoting effect on the reaction, resulting in a yield of the intermediate N-benzyl noradrenaline ketone hydrochloride of only 60%-70%, which significantly reduces the economy of the overall process and the utilization efficiency of raw materials. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing norepinephrine bitartrate to solve the problems raised in the above background technology.

[0005] A method for preparing norepinephrine bitartrate comprises the following steps:

[0006] Step A: catechol and N-benzylglycine undergo condensation reaction in a solvent under the action of an activator to obtain N-benzyl norepinephrine hydrochloride;

[0007] Step B: catalytic hydrogenation and deprotection to convert into racemic norepinephrine;

[0008] Step C: reacting with L-tartaric acid to obtain the norepinephrine bitartrate;

[0009] The activator is at least one of trifluoroacetic anhydride and dichlorodicyanobenzoquinone.

[0010] Preferably, in step A, the mass ratio of catechol, N-benzylglycine and solvent is 1:(1.3-1.8):(2.5-3.5).

[0011] Preferably, the solvent in step A is chloroform.

[0012] Preferably, in step A, the ratio of catechol to activator is 1 g:(0.005-0.008 mol).

[0013] Preferably, the catalyst in step B is a palladium-carbon catalyst.

[0014] Preferably, in step B, the mass ratio of N-benzyl norepinephrine hydrochloride to the catalyst is 1:(0.03-0.07).

[0015] Preferably, in step B, the pressure during the catalytic hydrogenation is controlled at 0.5-0.9 MPa, and the reaction is carried out for 4-8 hours.

[0016] Preferably, in step C, the molar ratio of racemic norepinephrine to L-tartaric acid is 1:(1.05-1.25).

[0017] The present invention achieves a significant improvement in the synthesis process of noradrenaline bitartrate by optimizing the activator system and reaction conditions. The present invention uses at least one of trifluoroacetic anhydride and dichlorodicyanobenzoquinone as an activator, which greatly improves the yield of the key intermediate N-benzyl noradrenaline ketone hydrochloride from 60%-70% to more than 80%. This improvement not only reduces the consumption and waste of raw materials, but also improves the economy of the overall process and the efficiency of raw material utilization. DETAILED DESCRIPTION

[0018] The following will be combined with the technical solutions in the embodiments of the present invention to clearly and completely describe. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0019] Palladium-carbon catalyst, palladium metal content 10% ± 0.2%, Yu Rui (Shanghai) Chemical Co., Ltd.

[0020] Embodiment 1:

[0021] The preparation method of norepinephrine bitartrate comprises the following steps:

[0022] Step A: Under nitrogen protection, add 300g of catechol, 495g of N-benzylglycine and 900g of chloroform to the reaction bottle, mix well and heat to reflux. Stir at 400rpm, add 1.95mol of trifluoroacetic anhydride, control the temperature to 60°C and maintain for 7 hours, during which thin layer chromatography. The volume ratio of the developing agent dichloromethane to methanol is 30:1, and the disappearance of catechol is detected. After the reaction is completed, add 700mL of water, stir at 300rpm for 30 minutes to mix, and stand for stratification. After the aqueous phase is adjusted to pH 8.5 with 15wt% ammonia water, cool to 5°C, and stir at 200rpm for crystallization for 3 hours. After the crystals are washed with purified water, they are transferred to 300g of anhydrous ethanol, heated to 65°C to dissolve, 15g of activated carbon is added for decolorization for 30 minutes, and filtered while hot. The filtrate was cooled to room temperature, and the pH value was adjusted to 1.5 with 35 wt % hydrogen chloride ethanol solution, stirred for 2 hours, filtered and vacuum dried to obtain N-benzyl norepinephrine ketone hydrochloride with a yield of 81.9%.

[0023] Step B: Under nitrogen protection, 300 g of N-benzyl norepinephrine ketone hydrochloride prepared in step A and 300 g of water were added to a hydrogenation reactor, stirred at 300 rpm at 50°C until completely dissolved, 15.2 g of palladium carbon catalyst was added, hydrogen was introduced after air was replaced in a sealed manner, the pressure was maintained at 0.7 MPa, the reaction was stirred at 400 rpm for 7 hours, the palladium carbon catalyst was recovered by filtration and washed with 50 g of water.

[0024] All the filtrate was transferred to a reaction bottle, 0.36 g of disodium ethylenediaminetetraacetate was added, and the mixture was stirred at 400 rpm for 20 minutes at 25 ° C. 15 wt% ammonia water was added dropwise to adjust the pH of the solution to 8.5. After the adjustment, the solution was cooled to 5 ° C and stirred at 300 rpm for crystallization for 1 hour. The obtained crystals were separated by centrifugation, and the filter cake was washed with purified water and anhydrous ethanol in turn, and vacuum dried at 50 ° C for 8 hours to obtain racemic norepinephrine with a yield of 64.5%.

[0025] Step C: Under nitrogen protection, add 100g of racemic norepinephrine obtained in step B, 100g of L-tartaric acid and 200g of water to the reaction bottle, stir and dissolve at 400rpm at 55℃. Add 5g of activated carbon, stir at 300rpm for 30 minutes to decolorize and filter while hot. The filtrate is cooled to 3℃ at a rate of 2℃ / min, stirred and crystallized at 300rpm for 5 hours, filtered and washed with 50g of anhydrous ethanol to obtain wet recrystallization. Add 100g of water to the wet recrystallization, stir and dissolve at 55℃ and 300rpm, decolorize with 3.3g of activated carbon for 30 minutes, filter while hot, cool the filtrate to 3℃ at 2℃ / min, stir and crystallize at 300rpm for 5 hours. Wash the crystals with 25g of anhydrous ethanol, dry them in vacuo at 45℃ for 5 hours, and obtain pure norepinephrine heavy tartaric acid with a yield of 28.5% and a purity of 99.6%.1 H NMR (Bruker, 400MHz, 298K, CDCl3, δ): 6.78–6.82(2H,m); 6.71–6.74(1H,m); 4.74–4.78(1H,m); 4.36–4.40(2H,d); 3.06–3.10(2H,m).

[0026] Embodiment 2:

[0027] Step A: Under nitrogen protection, add 300g of catechol, 495g of N-benzylglycine and 900g of chloroform to the reaction bottle, mix well and heat to reflux. Stir at 400rpm, add 1.95mol of dichlorodicyanobenzoquinone, control the temperature to 60°C and maintain for 7 hours, during which thin layer chromatography. The volume ratio of the developing agent dichloromethane to methanol is 30:1, and the catechol disappears. After the reaction is completed, add 700mL of water, stir at 300rpm for 30 minutes to mix, and stand for stratification. After the aqueous phase is adjusted to pH 8.5 with 15wt% ammonia water, cool to 5°C, and stir at 200rpm for crystallization for 3 hours. After the crystals are washed with purified water, transfer to 300g of anhydrous ethanol, heat to 65°C to dissolve, add 15g of activated carbon for decolorization for 30 minutes, and filter while hot. The filtrate was cooled to room temperature, and the pH was adjusted to 1.5 with 35% hydrochloric acid ethanol. The mixture was stirred for 2 hours, filtered and dried under vacuum to obtain N-benzyl norepinephrine ketone hydrochloride with a yield of 80.3%.

[0028] The only difference between Example 2 and Example 1 is that 1.95 mol of trifluoroacetic anhydride in step A is adjusted to 1.95 mol of dichlorodicyanobenzoquinone.

[0029] Embodiment 3:

[0030] Step A: Under nitrogen protection, add 300g of catechol, 495g of N-benzylglycine and 900g of chloroform to the reaction bottle, mix well and heat to reflux. Stir at 400rpm, add 1.5mol of phosphorus oxychloride and 0.45mol of dichlorodicyanobenzoquinone at a rate of 3mL per minute, control the temperature to 60°C and maintain for 7 hours, and perform thin layer chromatography during this period. The volume ratio of the developing agent dichloromethane to methanol is 30:1, and the catechol disappears. After the reaction is completed, add 700mL of water, stir at 300rpm for 30 minutes to mix, and stand for stratification. After the aqueous phase is adjusted to pH 8.5 with 15wt% ammonia water, cool to 5°C, and stir at 200rpm for crystallization for 3 hours. After the crystals are washed with purified water, transfer to 300g of anhydrous ethanol, heat to 65°C to dissolve, add 15g of activated carbon for decolorization for 30 minutes, and filter while hot. The filtrate was cooled to room temperature, and the pH was adjusted to 1.5 with 35% hydrogen chloride ethanol. The mixture was stirred for 2 hours, filtered and dried in vacuo to obtain N-benzyl norepinephrine ketone hydrochloride with a yield of 84.0%.

[0031] The only difference between Example 3 and Example 1 is that 1.95 mol of trifluoroacetic anhydride in step A is adjusted to 1.5 mol of phosphorus oxychloride and 0.45 mol of dichlorodicyanobenzoquinone.

[0032] Embodiment 4:

[0033] The difference between Example 4 and Example 3 is that the 1.5 mol of phosphorus oxychloride and 0.45 mol of dichlorodicyanobenzoquinone in step A are adjusted to 1.0 mol of phosphorus oxychloride and 0.95 mol of dichlorodicyanobenzoquinone. N-Benzyl noradrenaline ketone hydrochloride, yield 83.5%.

[0034] Embodiment 5:

[0035] The difference between Example 5 and Example 3 is that the 1.5 mol of phosphorus oxychloride and 0.45 mol of dichlorodicyanobenzoquinone in step A are adjusted to 1.25 mol of phosphorus oxychloride and 0.7 mol of dichlorodicyanobenzoquinone. N-Benzyl noradrenaline ketone hydrochloride, yield 85.6%.

[0036] Comparative Example 1:

[0037] Step A: Under nitrogen protection, add 300g of catechol, 495g of N-benzylglycine and 900g of chloroform to the reaction bottle, mix well and heat to reflux. Stir at 400rpm, add 1.95mol of phosphorus oxychloride at a rate of 3mL per minute, control the temperature to 60°C and maintain for 7 hours, and perform thin layer chromatography during this period. The volume ratio of the developing agent dichloromethane to methanol is 30:1, and the catechol disappears. After the reaction is completed, add 700mL of water, stir at 300rpm for 30 minutes to mix, and stand for stratification. After the aqueous phase is adjusted to pH 8.5 with 15wt% ammonia water, cool to 5°C, and stir at 200rpm for crystallization for 3 hours. After the crystals are washed with purified water, transfer to 300g of anhydrous ethanol, heat to 65°C to dissolve, add 15g of activated carbon for decolorization for 30 minutes, and filter while hot. The filtrate was cooled to room temperature, and the pH was adjusted to 1.5 with 35% hydrogen chloride ethanol, stirred for 2 hours, filtered and vacuum dried to obtain N-benzyl norepinephrine ketone hydrochloride with a yield of 63.5%.

[0038] The difference between Comparative Example 1 and Example 1 is that the 1.95 mol trifluoroacetic anhydride in step A is adjusted to 1.95 mol phosphorus oxychloride.

[0039] Comparative Example 2:

[0040] Step A: Under nitrogen protection, add 300g of catechol, 495g of N-benzylglycine and 900g of chloroform to the reaction bottle, mix well and heat to reflux. Stir at 400rpm, add 1.95mol of dichlorothionyl at a rate of 3mL per minute, control the temperature to 60°C and maintain for 7 hours, and perform thin layer chromatography during this period. The volume ratio of the developing agent dichloromethane to methanol is 30:1, and the catechol disappears. After the reaction is completed, add 700mL of water, stir at 300rpm for 30 minutes to mix, and stand for stratification. After the aqueous phase is adjusted to pH 8.5 with 15wt% ammonia water, cool to 5°C, and stir at 200rpm for crystallization for 3 hours. After the crystals are washed with purified water, transfer to 300g of anhydrous ethanol, heat to 65°C to dissolve, add 15g of activated carbon for decolorization for 30 minutes, and filter while hot. The filtrate was cooled to room temperature, and the pH was adjusted to 1.5 with 35% hydrochloric acid ethanol. The mixture was stirred for 2 hours, filtered and dried in vacuo to obtain N-benzyl norepinephrine ketone hydrochloride with a yield of 58.8%.

[0041] The difference between Comparative Example 2 and Example 1 is that the 1.95 mol trifluoroacetic anhydride in step A is adjusted to 1.95 mol thionyl chloride.

[0042] In Examples 1-5, the present invention improves the yield of the key intermediate N-benzyl noradrenaline ketone hydrochloride by selecting trifluoroacetic anhydride and / or dichlorodicyanobenzoquinone as activators. Compared with the traditional activators phosphorus oxychloride and dichlorothionyl used in Comparative Examples 1-2, these two activators show higher activity under the reaction conditions optimized by the present invention, thereby improving the reaction efficiency and the yield of the target intermediate product. Through this technical improvement, the yield of the intermediate product is increased from 63.5% to more than 80%.

[0043] In embodiment 3-5, the compounding of trifluoroacetic anhydride and dichlorodicyanobenzoquinone significantly improves the yield of N-benzyl noradrenaline ketone hydrochloride, and the effect is better than the case of using any activator alone in embodiment 1-2. The possible mechanism is that trifluoroacetic anhydride accelerates the reaction process by efficiently activating the carboxylic acid group, while dichlorodicyanobenzoquinone shows higher selectivity for the condensation reaction of phenolic compounds. The two activators may form a synergistic effect in the reaction, which not only improves the reaction rate, but also optimizes the efficiency and yield of product generation, thereby realizing a more efficient chemical synthesis process. As a preferred scheme, the activator is composed of trifluoroacetic anhydride and dichlorodicyanobenzoquinone in a molar ratio of (10-16): (4-10).

Claims

1. A method for preparing norepinephrine bitartrate, characterized in that: The steps include: Step A: catechol and N-benzylglycine undergo condensation reaction in a solvent under the action of an activator to obtain N-benzyl norepinephrine hydrochloride; Step B: catalytic hydrogenation and deprotection to convert into racemic norepinephrine; Step C: reacting with L-tartaric acid to obtain the norepinephrine bitartrate; The activator is at least one of trifluoroacetic anhydride and dichlorodicyanobenzoquinone.

2. The method for preparing norepinephrine bitartrate according to claim 1, wherein In step A, the mass ratio of catechol, N-benzylglycine and solvent is 1:(1.3-1.8):(2.5-3.5).

3. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: The solvent in step A is chloroform.

4. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: The dosage ratio of catechol to activator in step A is 1g:(0.005-0.008mol).

5. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: The catalyst in step B is a palladium-carbon catalyst.

6. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: In step B, the mass ratio of N-benzyl norepinephrine hydrochloride to the catalyst is 1:(0.03-0.07).

7. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: In step B, the pressure during catalytic hydrogenation is controlled at 0.5-0.9 MPa and the reaction is carried out for 4-8 hours.

8. The method for preparing norepinephrine bitartrate according to claim 1, characterized in that: In step C, the molar ratio of racemic norepinephrine to L-tartaric acid is 1:(1.05-1.25).