CN114394907A - Preparation method of noradrenaline bitartrate - Google Patents

Preparation method of noradrenaline bitartrate Download PDF

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CN114394907A
CN114394907A CN202210245021.4A CN202210245021A CN114394907A CN 114394907 A CN114394907 A CN 114394907A CN 202210245021 A CN202210245021 A CN 202210245021A CN 114394907 A CN114394907 A CN 114394907A
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noradrenaline bitartrate
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罗开伟
李冬明
毛兴波
徐骥
汪伟
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Fuan Pharmaceutical Group Ningbo Team Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention relates to a preparation method of noradrenaline bitartrate, which takes 3, 4-dibenzyloxyacetophenone as an initial raw material, and sequentially carries out bromination reaction and substitution reaction to obtain an intermediate 2, the intermediate 2 reacts with a reducing agent and a catalyst to obtain an intermediate 3, the intermediate 3 is resolved by D-tartaric acid to obtain an intermediate 4, and finally the intermediate 4 and L-tartaric acid form a salt to obtain noradrenaline bitartrate. The raw materials and auxiliary materials used in the invention are all cheap and easily available, the use of highly toxic and explosive reagents is avoided in the reaction process, the whole reaction route is moderate, the operation is simple and convenient, the reaction condition is mild and safe, the yield of the obtained finished product noradrenaline bitartrate is high, the quality is good, and the industrial production is favorably realized.

Description

Preparation method of noradrenaline bitartrate
Technical Field
The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of noradrenaline bitartrate.
Background
Norepinephrine bitartrate is an alpha, beta-receptor agonist for adrenergic receptors. Compared with adrenaline, the alpha-receptor has stronger actions of contracting blood vessels and increasing pressure, reflexively causes the heart rate to be slowed down, but excites the heart and has weaker action of expanding bronchus. It is mainly used for treating shock, such as shock caused by anesthesia, toxic shock, cardiogenic shock, etc. It was first marketed in the united states by Hospira inc in 1982, month 1.
At present, few reports exist in the synthetic routes of noradrenaline bitartrate, and the routes have problems in industrial application, such as expensive and not easily available starting materials, long process route, complicated operation, use of highly toxic or potentially explosive reagents in unit synthetic reaction, and the like.
The existing mainly relevant synthetic routes are reported as follows:
(1) in the reported route of Liangda Wei and Wangyue autumn, the norepinephrine bitartrate is obtained by taking chloroacetylcatechol as a starting material and sequentially carrying out ammoniation, catalytic hydrogenation and L-tartaric acid resolution. Although the reaction steps are few, the yield is low, the unprotected hydroxyl directly undergoes the subsequent reaction and is easy to oxidize and deteriorate, so that the purity of the final product is low, the quality cannot meet the requirement, and the method is not suitable for industrial production;
(2) U.S. Pat. No. 3,2774789 reports a resolution method of a norepinephrine racemate, but a synthesis method of the racemate is not mentioned, so the reference is not significant;
(3) j Am Chem Soc reports that catechol is used as an initial raw material, and is subjected to chloroacetyl chloride Friedel-crafts acylation, hydroxyl acetylation, bromination and drape Rayler reaction, and finally hydrochloric acid is hydrolyzed to obtain norketone hydrochloride, and the subsequent preparation of norracemate and finished products is not mentioned. The reaction steps of the route are longer, the yield is lower, the post-treatment is more complicated, and therefore the method has small industrial application prospect.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a preparation method of noradrenaline bitartrate, which has low production cost, short reaction route, good reaction safety and high quality of the obtained product.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of noradrenaline bitartrate comprises the following steps:
(1) carrying out bromination reaction on 3, 4-dibenzyloxyacetophenone and a bromination reagent in an organic solvent to obtain an intermediate 1;
Figure BDA0003530040050000021
(2) the intermediate 1 reacts with urotropine in an organic solvent at a certain temperature and time to generate quaternary ammonium salt, is not separated, and is hydrolyzed at a certain temperature for a period of time to obtain an intermediate 2;
Figure BDA0003530040050000022
(3) reducing carbonyl and removing benzyl of the intermediate 2 in an organic solvent under the action of a metal catalyst and a reducing agent to obtain an intermediate 3;
Figure BDA0003530040050000023
(4) resolving the intermediate 3 in a solvent by using a certain chiral resolving agent to obtain an intermediate 4 (R-norepinephrine);
Figure BDA0003530040050000024
(5) salifying the intermediate 4 with L-tartaric acid in a certain solvent to obtain noradrenaline bitartrate,
Figure BDA0003530040050000025
preferably, in the step (1), the brominating reagent in the bromination reaction is any one of bromine, copper bromide and tetrabutylammonium tribromide, preferably copper bromide; the raw material molar ratio of the 3, 4-dibenzyloxyacetophenone to the bromination reagent is 1: 1-2.5; the temperature of the bromination reaction is 20-40 ℃, and the reaction time is 3-5 h.
Preferably, in the step (1), the organic solvent used in the bromination reaction is a mixture of one or more solvents selected from methanol, ethanol, chloroform, dichloromethane, ethyl acetate and tetrahydrofuran, preferably dichloromethane, and the amount of the organic solvent is 5-10 times of the mass of the 3, 4-dibenzyloxyacetophenone.
Preferably, in the step (2), the organic solvent used in the substitution reaction is any one of methanol, ethanol, isopropanol, n-butanol, acetonitrile, ethyl acetate and chloroform, preferably chloroform, and the amount of the organic solvent is 5-10 times of that of the intermediate 1; the organic solvent for hydrolysis is methanol, ethanol and isopropanol, preferably ethanol; the raw material molar ratio of the intermediate 1 to urotropine and hydrochloric acid is 1 (1-2): (1-10); the temperature of the substitution reaction is 20-40 ℃, and the reaction time is 3-5 h; the temperature of the hydrolysis reaction is 60-80 ℃, and the reaction time is 1-2 h.
Preferably, in the step (3), the organic solvent is any one of methanol and ethanol, preferably methanol; the dosage of the organic solvent is 5-20 times of the mass of the intermediate 2.
Preferably, in the step (3), the reducing agent is hydrogen,Any one of amine formates; the catalyst is Pd (OH)2Any one of Pd/C, Pd/C, preferably Pd/C; the dosage of the catalyst is 1-10% of the mass of the intermediate 2; the reaction pressure is 0.3-1.0 MPa; the reaction temperature is 30-60 ℃.
Preferably, in the step (4), the solvent used in the resolution process is any one of methanol, ethanol, isopropanol and acetone, preferably methanol, and the amount of the solvent is 10-20 times of the mass of the intermediate 3.
Preferably, in the step (4), the resolving agent used in the resolving process is any one of L-tartaric acid, D-tartaric acid, L-mandelic acid and D-mandelic acid, preferably D-tartaric acid, and the using amount of the resolving agent is 1-2 times of the mass of the intermediate 3; the splitting temperature is 20-30 ℃, and the splitting time is 8-24 h.
Preferably, in the step (5), the solvent used in the salt forming process is any one of methanol-water (10:1v/v), ethanol-water (10:1v/v) and isopropanol-water (10:1v/v), and preferably methanol-water (10:1 v/v); the dosage of the L-tartaric acid is 5-30 times of the mass of the intermediate 4, the dosage of the L-tartaric acid is 1-2 times of the mass of the intermediate 4, the salt forming temperature is 0-10 ℃, and the salt forming time is 8-24 hours.
Compared with the prior art, the invention has the advantages that: the raw materials and auxiliary materials used in the invention are all cheap and easily available, the use of highly toxic and explosive reagents is avoided in the reaction process, the whole reaction route is moderate, the operation is simple and convenient, the reaction condition is mild and safe, the yield of the obtained finished product noradrenaline bitartrate is high, the quality is good, and the industrial production is favorably realized.
Drawings
FIG. 1 is a reaction scheme of various embodiments of the present invention;
FIG. 2 shows the preparation of intermediate 1 obtained in example 1 of the present invention1H-NMR spectrum;
FIG. 3 is a drawing showing the preparation of intermediate 2 obtained in example 1 of the present invention1H-NMR spectrum;
FIG. 4 shows the preparation of intermediate 3 obtained in example 1 of the present invention1H-NMR spectrum;
FIG. 5 shows noradrenaline bitartrate obtained in example 1 of the present invention1H-NMR spectrum.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
The reaction mechanism of the present invention is shown in FIG. 1.
Example 1:
the preparation method of noradrenaline bitartrate in the embodiment comprises the following steps:
(1) preparation of intermediate 1
At room temperature, 180.0g (0.54mol) of 3, 4-dibenzyloxyacetophenone and 900mL of methylene chloride were added to a reaction vessel, and after stirring and dissolution, 302g (1.35mol) of copper bromide was added to the reaction vessel, followed by stirring and reaction for 3 hours under reflux. And (3) carrying out suction filtration on the reaction solution, washing the filtrate by using concentrated hydrochloric acid, separating an organic layer, and carrying out reduced pressure distillation on the organic layer to remove dichloromethane. And adding 600mL of methanol into the residue, refluxing for 0.5h, stirring and cooling to 0-5 ℃, keeping the temperature and stirring for 1h, performing suction filtration, leaching the filter cake with a proper amount of methanol, and drying to obtain 188.7g of off-white solid, namely the intermediate 1, as shown in figure 2, wherein the yield is 85%.
(2) Preparation of intermediate 2
At room temperature, 180.0g (0.44mol) of intermediate 1, 900mL of chloroform and 67.0g of urotropin are added into a reaction vessel, and stirred for 3 hours at 20-30 ℃. After the reaction is finished, adding 1L of ethanol and 250ml of hydrochloric acid into the reaction solution, carrying out reflux reaction for 2h, cooling to 20-30 ℃, carrying out suction filtration, washing a filter cake with ice water and ethanol, and drying the filter cake under reduced pressure to obtain 134.0g of intermediate 2, wherein the yield is 80% as shown in FIG. 3.
(3) Preparation of intermediate 3
40.0g (0.025mol) of intermediate 2, 600ml of methanol, and 5.0g of 10% Pd/C were put into a 1L hydrogenation reactor, and the mixture was stirred at 40 to 50 ℃ under a hydrogen atmosphere of 0.6MPa until hydrogen absorption was stopped. And (3) removing palladium carbon by suction filtration, dropwise adding 35.0g of ammonia water into the filtrate at the temperature of 0-10 ℃, stirring and crystallizing for 0.5h, suction filtering, washing with water and methanol, and drying the filter cake under reduced pressure to obtain 17.3g of an intermediate 3, wherein the yield is 98% as shown in figure 4.
(4) Preparation of intermediate 4
Adding 20.0g (0.12mol) of intermediate 3, 26.0g (0.17mol) of D-tartaric acid and 400ml of methanol into a reaction bottle, stirring for dissolving, stirring for reacting for 16h at 20-30 ℃, precipitating a solid, performing suction filtration, dissolving the obtained filter cake with 100ml of water, adjusting the pH value to be 9 by using ammonia water, precipitating a solid, performing suction filtration, and repeating the step for 2 times to obtain 8.5g of intermediate 4 with the yield of 42%.
(5) Synthesis of noradrenaline bitartrate:
adding 10.0g (0.06mol) of the intermediate 4, 10.0g (0.066mol) of L-tartaric acid and 20ml of water into a reaction bottle, stirring for dissolving, adding 200ml of methanol, stirring for reacting for 16h at 0-10 ℃, separating out a solid, performing suction filtration, washing a filter cake with methanol, and drying to obtain 17.0g of noradrenaline bitartrate, wherein the yield is 85% as shown in figure 5.
Example 2:
the preparation method of noradrenaline bitartrate in the embodiment comprises the following steps:
(1) preparation of intermediate 1
At room temperature, adding 180.0g (0.54mol) of 3, 4-dibenzyloxyacetophenone and 1000mL of chloroform into a reaction vessel, stirring to dissolve, then adding 130.0g (0.81mol) of bromine dropwise, and stirring for 3h under the reflux condition after dropwise addition. The reaction solution was washed with water and saturated sodium bicarbonate, and the organic layer was separated and evaporated under reduced pressure to remove chloroform. And adding 600mL of methanol into the residue, refluxing for 0.5h, stirring and cooling to 0-5 ℃, preserving heat and stirring for 1h, performing suction filtration, leaching the filter cake with methanol, and drying to obtain 120.0g of off-white solid, namely the intermediate 1, with the yield of 53%.
(2) Preparation of intermediate 2
Adding 180.0g (0.44mol) of intermediate 1, 600mL of ethanol and 67.0g of urotropine into a reaction vessel at room temperature, and stirring for 3 hours at 20-30 ℃. And after the reaction is finished, adding 250ml of hydrochloric acid, carrying out reflux reaction for 2h, cooling to 20-30 ℃, continuing stirring for 30min, carrying out suction filtration, washing a filter cake with ice water and ethanol, and drying the filter cake under reduced pressure to obtain 105.0g of intermediate 2 with the yield of 62%.
(3) Preparation of intermediate 3
Adding 40.0g (0.025mol) of the intermediate 2, 600ml of ethanol and 5.0g of 10% Pd/C into a hydrogenation kettle, stirring and reacting at 40-50 ℃ under the hydrogen atmosphere of 0.6MPa until no more hydrogen is absorbed, performing suction filtration to remove palladium carbon, dripping 35.0g of ammonia water into filtrate at 0-10 ℃, performing stirring and crystallization for 0.5h, performing suction filtration, washing with water and methanol, and performing reduced pressure drying on filter cakes to obtain 14.1g of the intermediate 3 with the yield of 80%.
(4) Preparation of intermediate 4
Adding 20.0g (0.12mol) of intermediate 3, 26.0g (0.17mol) of D-tartaric acid and 400ml of acetone into a reaction flask, stirring for dissolving, stirring for reacting for 16h at 20-30 ℃, precipitating a solid, performing suction filtration, dissolving the obtained filter cake with 100ml of water, adjusting the pH value to 9 with ammonia water, precipitating a solid, performing suction filtration, and repeating the steps for 2 times to obtain 4.2g of intermediate 4 with the yield of 21%.
(5) Synthesis of noradrenaline bitartrate:
adding 10.0g (0.06mol) of the intermediate 4, 10.0g (0.066mol) of L-tartaric acid and 20ml of water into a reaction bottle, stirring for dissolving, adding 200ml of ethanol, stirring for reacting for 16h at 0-10 ℃, separating out a solid, performing suction filtration, washing a filter cake with methanol, and drying to obtain 11.6g of noradrenaline bitartrate with the yield of 58%.
Example 3:
the preparation method of noradrenaline bitartrate in the embodiment comprises the following steps:
(1) preparation of intermediate 1
At room temperature, 180.0g (0.54mol) of 3, 4-dibenzyloxyacetophenone and 900mL of methylene chloride were added to a reaction vessel, and after stirring and dissolution, 650.2g (1.35mol) of tetrabutylammonium tribromide was added to the reaction vessel, and the reaction was stirred under reflux for 3 hours. The reaction mixture was washed with hydrochloric acid and water, and the organic layer was separated and the dichloromethane was distilled off under reduced pressure. And adding 600mL of methanol into the residue, refluxing for 0.5h, stirring and cooling to 0-5 ℃, keeping the temperature and stirring for 1h, performing suction filtration, leaching the filter cake with a proper amount of methanol, and drying to obtain 150.0g of off-white solid, namely the intermediate 1, with the yield of 67%.
(2) Preparation of intermediate 2
At room temperature, 180.0g (0.44mol) of intermediate 1, 900mL of chloroform and 67.0g of urotropin are added into a reaction vessel, and stirred for 3 hours at 20-30 ℃. After the reaction is finished, adding 1L of ethanol and 150ml of hydrochloric acid into the reaction solution, carrying out reflux reaction for 2h, cooling to 20-30 ℃, carrying out suction filtration, washing a filter cake with ice water and ethanol, and drying the filter cake under reduced pressure to obtain 114.0g of intermediate 2 with the yield of 67%.
(3) Preparation of intermediate 3
40.0g (0.025mol) of intermediate 2, 600ml of methanol, and 5.0g of 10% Pd/C were put into a 1L hydrogenation reactor, and the mixture was stirred at 30 to 40 ℃ under a hydrogen atmosphere of 0.3MPa until hydrogen absorption was stopped. And (3) removing palladium carbon by suction filtration, dropwise adding 35.0g of ammonia water into the filtrate at the temperature of 0-10 ℃, stirring and crystallizing for 0.5h, suction filtering, washing with water and methanol, and drying the filter cake under reduced pressure to obtain 13.2g of an intermediate 3 with the yield of 75%.
(4) Preparation of intermediate 4
Adding 20.0g (0.12mol) of intermediate 3, 26.0g (0.17mol) of D-tartaric acid and 400ml of ethanol into a reaction bottle, stirring for dissolving, stirring for reacting for 16h at 20-30 ℃, precipitating a solid, performing suction filtration, dissolving the obtained filter cake with 100ml of water, adjusting the pH value to be 9 by using ammonia water, precipitating the solid, performing suction filtration, and repeating the steps for 2 times to obtain 5.3g of intermediate 4 with the yield of 26%.
(5) Synthesis of noradrenaline bitartrate:
adding 10.0g (0.06mol) of the intermediate 4, 10.0g (0.066mol) of L-tartaric acid and 20ml of water into a reaction bottle, stirring for dissolving, adding 200ml of acetone, stirring for reacting for 16h at 0-10 ℃, separating out a solid, performing suction filtration, washing a filter cake with methanol, and drying to obtain 14.0g of noradrenaline bitartrate with the yield of 70%.

Claims (10)

1. A preparation method of noradrenaline bitartrate is characterized by comprising the following steps:
(1) carrying out bromination reaction on 3, 4-dibenzyloxyacetophenone and a bromination reagent in an organic solvent to obtain an intermediate 1;
Figure FDA0003530040040000011
(2) the intermediate 1 reacts with urotropine in an organic solvent to generate quaternary ammonium salt, is not separated, and is hydrolyzed to obtain an intermediate 2;
Figure FDA0003530040040000012
(3) reducing carbonyl and removing benzyl of the intermediate 2 in an organic solvent under the action of a metal catalyst and a reducing agent to obtain an intermediate 3;
Figure FDA0003530040040000013
(4) the intermediate 3 is resolved in a solvent by a chiral resolving agent to obtain an intermediate 4;
Figure FDA0003530040040000014
(5) salifying the intermediate 4 with L-tartaric acid in a solvent to obtain a target product noradrenaline bitartrate,
Figure FDA0003530040040000015
2. the method for producing noradrenaline bitartrate according to claim 1, characterized in that: in the step (1), the brominating reagent is any one of bromine, copper bromide and tetrabutylammonium tribromide.
3. The method for producing noradrenaline bitartrate according to claim 1, characterized in that: in the step (1), the raw material molar ratio of the 3, 4-dibenzyloxyacetophenone to the bromination reagent is 1 (1-2.5); the temperature of the bromination reaction is 20-40 ℃, and the reaction time is 3-5 h.
4. The method for producing noradrenaline bitartrate according to claim 1, characterized in that: in the step (1), the organic solvent in the bromination reaction is any one or a mixture of a plurality of solvents selected from methanol, ethanol, chloroform, dichloromethane, ethyl acetate and tetrahydrofuran, and the amount of the organic solvent is 5-10 times of the mass of the 3, 4-dibenzyloxyacetophenone.
5. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (2), the organic solvent used in the substitution reaction is any one of methanol, ethanol, isopropanol, n-butanol, acetonitrile, ethyl acetate and chloroform, and the dosage of the organic solvent is 5-10 times of that of the intermediate 1; the organic solvent used for hydrolysis is any one of methanol, ethanol and isopropanol; the molar ratio of the intermediate 1 to the materials of urotropine and hydrochloric acid is 1 (1-2) to 1-10; the temperature of the substitution reaction is 20-40 ℃, and the reaction time is 3-5 h; the temperature of the hydrolysis reaction is 60-80 ℃, and the reaction time is 1-2 h.
6. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (3), the organic solvent is any one of methanol and ethanol; the dosage of the organic solvent is 5-20 times of the mass of the intermediate 2.
7. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (3), the reducing agent is any one of hydrogen and ammonium formate; the catalyst is Pd (OH)2And Pd/C, Pd/C; the dosage of the catalyst is 1-10% of the mass of the intermediate 2; the reaction pressure is 0.3-1.0 MPa, and the reaction temperature is 30-60 ℃.
8. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (4), the solvent used in the resolution process is any one of methanol, ethanol, isopropanol and acetone, and the amount of the solvent is 10-20 times of the mass of the intermediate 3.
9. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (4), the resolving agent used in the resolving process is any one of L-tartaric acid, D-tartaric acid, L-mandelic acid and D-mandelic acid, and the using amount of the resolving agent is 1-2 times of the mass of the intermediate 3; the splitting temperature is 20-30 ℃, and the splitting time is 8-24 h.
10. The method for producing noradrenaline bitartrate according to any one of claims 1 to 4, characterized in that: in the step (5), the solvent used in the salt forming process is any one of a methanol-water mixed solvent, an ethanol-water mixed solvent and an isopropanol-water mixed solvent with a volume ratio of 10: 1; the dosage of the L-tartaric acid is 5-30 times of the mass of the intermediate 4, the dosage of the L-tartaric acid is 1-2 times of the mass of the intermediate 4, the salt forming temperature is 0-10 ℃, and the salt forming time is 8-24 hours.
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CN116162034A (en) * 2022-12-23 2023-05-26 蚌埠丰原医药科技发展有限公司 Chiral resolution method of racemic norepinephrine
CN115850095A (en) * 2022-12-27 2023-03-28 武汉嘉诺康医药技术有限公司 Preparation method of noradrenaline bitartrate
CN116410096A (en) * 2023-02-23 2023-07-11 河北广祥制药有限公司 Preparation method of norepinephrine bitartrate

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