WO2017211129A1

WO2017211129A1 - Method for manufacturing ephedrine or pseudoephedrine and ephedrine or pseudoephedrine intermediate

Info

Publication number: WO2017211129A1
Application number: PCT/CN2017/080841
Authority: WO
Inventors: 王哲清; 葛萌芽; 叶增芳; 舒理建; 曾亮荣; 方梅芬; 孙云雷; 张柯华
Original assignee: 浙江普洛康裕制药有限公司
Priority date: 2016-06-07
Filing date: 2017-04-18
Publication date: 2017-12-14
Also published as: CN106008183B; CN106008183A

Abstract

A method for manufacturing an ephedrine or pseudoephedrine intermediate, comprising: using 2-chloropropionyl chloride and benzene as starting raw materials and performing a Friedel-Crafts reaction using a Lewis acid catalyst to generate 2-chloro-1-phenyl-1-propanone; and reacting the generated 2-chloro-1-phenyl-1-propanone and methylamine in an aprotic solvent to generate 2-methylamino-1-phenyl-1-propanone. Further provided is a method for manufacturing ephedrine or pseudoephedrine. The method does not use the highly polluting phosphorus trichloride, and does not use the extremely hazardous and expensive bromine. The Friedel-Crafts reaction and amination reaction are completed within a single solution, reducing infrastructure cost. The invention thereby provides a safe, simple, low cost, and environment-friendly method for synthesizing ephedrine and pseudoephedrine.

Description

Method for preparing ephedrine or pseudoephedrine and ephedrine or pseudoephedrine intermediate

Technical field

The invention belongs to the field of medicine and chemical industry, and particularly relates to a preparation method of an ephedrine or pseudoephedrine and an intermediate of ephedrine or pseudoephedrine.

Background technique

Ephedra is a wild plant that has been used for sweating and asthma in Chinese medicine for thousands of years. In 1885, Japanese scholar Chang Changyi first separated the mixture of active ingredients from the plant of Ephedra, and its main component was ephedrine. In 1889, Merck Pharmaceuticals isolated pure ephedrine and pseudoephedrine from European ephedra plants. In 1949, Freudenberg and 1950, Brewster et al. determined the absolute configuration of the two, as shown in the following equation:

Although both compounds can now be produced by synthetic methods, China still harvests 30,000 tons of ephedra plants every year, extracting extracts for internal use and exporting. Such huge consumption has seriously damaged the vegetation in the northwest, which is one of the causes of sandstorms.

In the field of Western medicine treatment, the two are widely used, and the demand is increasing year by year.

Ephedrine is used as an adrenergic agonist in hospitals. It has the function of contracting blood vessels and relaxing the respiratory bronchus. It can be used to prevent blood pressure drop, treat nasal congestion, relieve bronchial asthma and allergic urticaria. Pseudoephedrine can be used to relieve mucous membrane congestion in the upper respiratory tract, and to breathe smoothly, so that it is widely used for the adjuvant treatment of colds and colds.

There are several different routes for the synthesis of these two drugs. The typical public reports include the following documents:

J.Org.Chem 1947, 12:506

Acta Chim Sci Hung 1958, 17:181

Tetrahedron Letters 2000, 41:953

Tetrahedron Letters 1989, 30:329

Synthesis 1990:573

The routes reported in these documents are not applicable to large-scale production in industry, which involves factors such as production costs, labor protection, and environmental protection. The other small part is not suitable for the domestic reagent supply and production equipment.

At present, the general production process at home and abroad is as shown in the following formula. The whole preparation process consists of six steps:

Reports of such chemical reactions can be found in the following journals and patent documents:

Chinese Journal of Pharmaceutical Industry 31 (12), 534-535, 2000

J.Med.Chem 52(21), 6768-6781, 2009

Forensic Science International 212 (1-3), 13-21, 2011

Analytical Chem. 85(19), 9400-9408, 2013

WO2010121002A1

CN104119240A

The above synthetic process has the following defects, which cannot meet the technical requirements, safety requirements and environmental protection requirements of modern industrial production:

First, phosphorous acid is formed in the first step reaction. The presence of large amounts of phosphorus-containing wastewater has created environmental pressures.

Secondly, the second step of the Friedel-Craft reaction for the preparation of propiophenone has been reported in the papers J. Am. Chem. Soc 1936, 58: 262-4 and patent document US 4,539,420, respectively. The yields were 66.4% and 86.3%, respectively. After the reaction was completed, the reaction mixture needed to be purified, and a considerable portion of the product was lost in complicated post-treatment and purification operations, such as multiple extractions of diethyl ether, positive and negative washing of water, and expensive Product adsorption during the drying of anhydrous magnesium sulfate and vaporization of the product during vacuum distillation. The crude product can only be used in the third step after being distilled.

In addition, the third step uses expensive bromine, which is a highly volatile liquid and is highly corrosive and often has accidents during transfer, storage and application. Since the bromination reaction uses only one bromine atom and the other bromine atom becomes hydrogen bromide (HBr) gas, the efficiency is lost, that is, the utilization of bromine is only one-half.

And because of the strong bromine activity, about 3% of the dibromo-substituted product is formed in this electrophilic reaction process, compound (3):

When the concentration of bromine in the localized portion of the reaction is too high or the agitation is poor and the temperature in the local region is too high, the ratio of this by-product rises.

Calculating costs based on the unit consumption of chemicals, bromine takes up 33% of the cost of raw materials. This does not include the complicated operation of purifying and removing by-products.

In the fourth step of the methylamine-substituted bromine reaction, an aqueous solution of sodium hydroxide is added to neutralize the hydrogen bromide gas generated in the reaction to promote the rapid completion of the reaction. However, in this process, since hydroxide (OH ^- ) itself is a strong nucleophilic reagent, another nucleophilic substitution reaction is inevitably accompanied, and a by-product 2-hydroxy-1-phenyl-acetone is formed. (4):

In addition, once 2-hydroxy-1-phenyl-acetone (4) is formed, tautomerization of 2-hydroxy-1-phenyl-acetone is formed in an alkaline environment over a period of equilibrium. Body, compound (5):

It can be seen that the methylation reaction is carried out in an aqueous solution of sodium hydroxide, and the methylamine is applied to the reaction in a 30-40% aqueous solution, which necessarily produces the desired 2-methylamino-1-phenyl-acetone and the two undesired pairs. The product 2-hydroxy-1-phenyl-acetone (4) and its isomer (5). The ratio of the three varies depending on the alkalinity, concentration, temperature and reaction time. The yield of the desired intermediate 2-methylamino-1-phenyl-acetone can fluctuate fiercely between 50-85%. In order to remove these two impurities, not only did it take time, but some products were lost during the purification process.

In view of the fact that it is considered to replace the bromine atom with a chlorine atom, it is one of the main starting points of the present invention to prepare 2-halo-1-phenyl-acetone to reduce the cost, reduce the formation of by-products, and ensure the safety of operation.

However, the activity of the chlorine atom at the alpha position of the carbonyl group is much smaller than the activity of the alpha-bromine atom. With the reaction of aqueous methylamine and 2-chloro-1-phenyl-acetone, even with sodium hydroxide, the reaction is still very difficult and very slow, often accompanied by some mixture of dark or black polymerization and hydrolysis. .

The substitution reaction can be carried out using an aqueous solution of methylamine and a strong α-bromine atom, but another external cause which is almost incapable of reacting with the slow-reactive α-chloride atom is the hydration effect of the methylamine molecule.

According to a study by Russian chemists, an article published in the Russian Chemical Bulletin 61(2): 240-247, 2012 reports that the first layer of water molecules formed near the CH ₃ - group in the CH ₃ NH ₂ molecule is 14.4 There are 6.9 first water molecules formed in the vicinity of the NH ₂ - group, and 6.9 water molecules forming an intermolecular hydrogen bond with the NH ₂ - group. In addition, these water molecules form hydrogen bonds with each other as if two barriers were formed to prevent the nitrogen atoms and the nitrogen atoms in the methylamine from contacting each other and reacting with each other.

In this external environment, the methylamine molecule is no longer a free-acting molecule, and the nitrogen atom in the NH ₂ - group is no longer a bare atom. It is difficult to attack the carbon atom of the α-position of the carbonyl to form 2- Methylamino-1-phenyl-acetone.

The fourth embodiment of the patent document published as CN101870660A mentions the methylation reaction using 2-chloro-1-phenyl-acetone as a starting material. The mixture was reacted with 165 ml of a methylamine aqueous solution and a 30% aqueous sodium hydroxide solution at 43 ° C for two hours, and the yield was 66%. Since the reaction conditions of this example are carried out in an aqueous solution, and water is the strongest protic solvent, and reacted for a further two hours with the participation of a strong base, a large amount of by-products are formed, which are tested by the inventors of the present application and described The results cannot be reproduced in the trial.

In the patent document published as WO2003091200A, it is described that 2-chloro-1-phenyl-acetone is reacted in a solution of 16% methylamine in DMF at 21 ° C for one hour, and the inventors claim that HPLC analysis shows that 99% of 2-methylamine is formed. Base-1-phenyl-acetone. However, this patent does not provide any detailed experimental procedures and data, and does not provide any reaction mixture treatment method and purification method. After the inventors' experimental test of the present application, the description results cannot be reproduced at all.

The reason is that the boiling point of DMF is as high as 152-154 ° C. After the end of the reaction, the DMF is distilled off under the usual heating under reduced pressure to prevent it from interfering with the next split operation. Prolonged heating promotes hydrolysis of the product, resulting in two by-products, nitrogen oxides (8) and double polymers (9). Therefore, after purification and removal of the two by-products, the reaction yield is lowered.

Compound (8) is an oxynitride.

Compound (9) is a 1,4-dihydropyrazine compound which is very stable and has been reported in the Journal of Chromatographic Science, 1994, 32:552.

In summary, the current production methods for the production of 2-methylamino-1-phenyl-acetone, the key intermediate of ephedrine and pseudoephedrine, are difficult to implement industrially, with high risk and cost. High technical problems with high environmental pollution.

Summary of the invention

The inventors of the present invention have drawbacks in the production process of the current key intermediates of ephedrine and pseudoephedrine, 2-chloro-1-phenyl-1-propanone and 2-methylamino-1-phenyl-1-propanone. Intensive and meticulous research has been carried out to invent a safe, inexpensive and simple green chemical process route that can be used for large-scale production.

The invention also provides a method for preparing ephedrine and pseudoephedrine, which has the advantages of simple steps, safety, low preparation cost, environmental protection and industrial production.

A preparation method of ephedrine or pseudoephedrine intermediate 2-chloro-1-phenyl-1-propanone comprises: using 2-chloropropionyl chloride and benzene as starting materials, and carrying out Fu-gram under Lewis acid catalysis The reaction yielded 2-chloro-1-phenyl-1-propanone.

The present invention first combines a Friedel-Craft acylation reaction and an α-halogenation reaction into a one-step reaction. Directly using 2-chloropropionyl chloride (Compound 10) as one of the raw materials and benzene to form 2-chloro-1-phenyl-1-propanone (Compound 6), no longer using phosphorus trichloride, the reaction process is as follows Show:

In the above Friedel-Craft reaction, benzene is preferably used as a reaction solvent for the Friedel-Craft reaction. At the same time, the inventors of the present invention found that the benzene which is intensively charged in this step reaction does not have to be distilled off and can be used as a reaction solvent for the next methylation, and this key change avoids the above-mentioned products in the post-treatment and The loss in purification, which not only increases the yield to 95-98%, eliminates time-consuming and labor-intensive post-treatment and purification operations, and saves benzene consumption by "one-size-fits-all".

In today's industrial production, 2-bromo-1-phenyl-1-propanone is produced by a two-step reaction of acylation and bromination. This is a highly volatile liquid that has a strong erosive effect on human mucous membranes such as the eyes, mouth, nasopharynx and genitals. The separation, extraction, stratification and distillation purification operations of the post-treatment after the reaction are completed pose a serious threat to worker safety and the workshop environment.

This compound (2-bromo-1-phenyl-1-propanone) is no longer produced in the present invention. The resulting 2-chloro-1-phenyl-1-propanone has no tearing action. After the reaction is completed, after a simple sealing treatment, it is not necessary to separate the product, and the benzene-free aqueous solution of the compound is transferred in a closed nitrogen-filled system. The methylation reaction is carried out directly into the next reactor. The combination of these two improvements eliminates the need for bromine, which not only greatly reduces raw material costs, but also poses no threat to workers' health and the work environment.

At the same time, since the bromine is not required, the above dibromo product (3) will not be produced:

In the above Friedel-Craft reaction, the molar ratio of the 2-chloropropionyl chloride to benzene is preferably 1: (2 to 50). Further preferably, the molar ratio of the 2-chloropropionyl chloride to benzene is 1: (2 to 5); if excess benzene is directly used in the subsequent methylation reaction. Preferably, the molar ratio of the 2-chloropropionyl chloride to benzene is 1: (2.5 to 5); if other aprotic solvents are used in the methylation reaction, the amount of benzene can be adjusted to be reduced as Preferably, the molar ratio of the 2-chloropropionyl chloride to benzene is 1: (1.5 to 2.5).

In the above Friedel-Craft reaction, preferably, the molar ratio of the 2-chloropropionyl chloride to the Lewis acid is 1: (1 to 5); and further preferably, the 2-chloropropionyl chloride and the Lewis acid are used. The molar ratio is 1: (1 to 1.5). The Lewis acid is selected from one or a mixture of two or more of ferric chloride and aluminum chloride. Further preferably, the Lewis acid is selected from aluminum chloride, and more preferably anhydrous aluminum chloride.

In the above Friedel-Craft reaction, the 2-chloropropionyl chloride is generally used in a batchwise manner, and the feed temperature is usually -5 to 10 °C, more preferably 0 to 5 °C. After the completion of the addition of 2-chloropropionyl chloride, the reaction is complete at 10 to 40 ° C, and the reaction time is usually 1 to 5 hours.

A method for preparing an ephedrine or pseudoephedrine intermediate 2-methylamino-1-phenyl-acetone, comprising:

2-Chloro-1-phenyl-1-propanone and methylamine produced by any of the above aspects are reacted in an aprotic solvent to give 2-methylamino-1-phenyl-1-propanone. The reaction process is as follows:

As a preferred embodiment, after completion of the Friedel-Crafts reaction, the Lewis acid catalyst is removed, and the organic phase is washed and directly reacted with methylamine, which serves as both a reaction solvent for the Friedel-Craft reaction and a raw material for the Friedel-Craft reaction.

Preferably, the above reaction is carried out under conditions of no oxygen, no water or no oxygen. Further preferably, the above reaction is carried out under anhydrous and anhydrous conditions. In the second step of the present invention, 2-chloro-1-phenyl-1-propanone and methylamine which are not active are reacted at room temperature under anhydrous, anaerobic and aprotic solvents. This reaction environment completely prevents the formation of methylamine hydrate or methylamine complex, so that the free-acting naked methylamine can more easily access the α-chloride atom, and smoothly complete the nucleophilic reaction to form 2-methylamino group- 1-phenyl-1-propanone (7).

The inventors of the present invention have found for the first time that if the methylamine molecule is dissolved in an aprotic solvent and in an anhydrous environment, a hydrated complex of methylamine is not formed, so that methylamine can directly attack the compound (6) carbonyl group. The alpha-chloride atom, which replaces the chlorine atom, forms the desired intermediate (7).

It has been confirmed by well-designed experiments that the aprotic solvent is selected from the group consisting of benzene, toluene, xylene, trimethylbenzene, C5-C12 linear alkanes, cyclopentane, cyclohexane, petroleum ether, dichloromethane, and chloroform. , dichloroethane, dichloroethylene, trichloroethylene, chlorobenzene, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, hexahydrocyclohexane, acetonitrile, N,N-dimethylformamide (DMF), One or more of dimethyl sulfoxide (DMSO), N-methylpyrrole (NMP), and the like. The C5-C12 linear alkane is preferably heptane, hexane or pentane. Protic solvents such as water, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol are not suitable for this methylation reaction.

There are two ways to prepare methylamine solutions for these solvents:

One is to atomize the above aprotic anhydrous solvent under nitrogen to purge oxygen. The methylamine gas is then bubbled under cooling to between -20 ° C and -5 ° C until a saturated solution is formed. The reaction was started by titration to determine the concentration of the methylamine solution followed by the addition of the calculated amount of 2-chloro-1-phenyl-acetone.

The other is to pass the methylamine gas into a pressure bottle pre-cooled to about -20 °C under nitrogen protection, collect liquid methylamine, and weigh. Then, a solution containing a predetermined amount of 2-chloro-1-phenyl-acetone pre-deaerated and previously cooled to about -20 ° C was added, and the pressure bottle was sealed, and the reaction was started by slowly raising the temperature to room temperature.

The yield of 2-methylamino-1-phenyl-acetone produced by the two preparation methods can be more than 95%, and almost no other impurities are formed, and the reaction product can be applied to the next step without purification treatment.

It is not necessary to use a 30% aqueous sodium hydroxide solution to neutralize the hydrogen bromide gas generated during this reaction. Accordingly, said alkaline hydrolysis will not occur. Therefore, it is impossible to form the by-product compound (4) and the compound (5).

Further, since the oxygen present in the reaction system is completely eliminated, the product compound (7) which has been formed is prevented from reacting with oxygen to form the nitrogen oxide compound (8). Further, due to the reaction at room temperature, the compound (7) does not have the opportunity to form an isomeric equilibrium and is dehydrated to form 1,4-dihydropyrazine (9).

Preferably, the molar ratio of the 2-chloro-1-phenyl-acetone to methylamine is 1:1 to 5. The molar ratio of 2-chloro-1-phenyl-acetone to methylamine is 1: (2.5-3.5), and methylamine is simultaneously used as an acid binding agent;

In order to reduce the unit consumption of the methylamine gas, an anhydrous base may be used instead of the methylamine used as an acid binding agent, and the alkali may be a carbonate and a hydrogencarbonate such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate or carbonic acid. One or more of sodium hydrogen, potassium hydrogencarbonate, calcium oxide, magnesium oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, a tertiary amine or a quaternary ammonium base. Further preferably, the base may be anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous calcium carbonate, anhydrous magnesium carbonate, anhydrous sodium hydrogencarbonate, anhydrous potassium hydrogencarbonate, anhydrous calcium oxide, anhydrous magnesium oxide, no One or more of water sodium hydroxide, anhydrous potassium hydroxide, anhydrous calcium hydroxide, anhydrous magnesium hydroxide, and the like. In this case, the molar ratio of the 2-chloro-1-phenyl-acetone to methylamine is preferably 1: (1.5 to 2.5).

Preferably, the above reaction can be carried out under normal pressure or under pressure. Preferably, the reaction pressure is carried out between 0-1 MPa. The reaction is carried out between -20 ° C and 100 ° C.

The methylation reaction yield of the step created by the invention can reach 93-97%, and the purity of 2-methylamino-1-phenyl-1-propanone can reach 98-99%.

The 2-methylamino-1-phenyl-1-propanone formed by the invention can be directly applied to the resolution of the optical isomer of the next step, or can be reacted with hydrochloric acid to form its hydrochloride salt, and after evaporation under reduced pressure. It can be stored in the warehouse stably and ready for use.

Through the above two novel aspects of the synthesis method and the improvement of the reaction conditions, that is, the substitution of the starting material of the Friedel-Craft acylation reaction, the change of the starting materials, reagents and reaction conditions of the methylation reaction not only enhances 2-A The yield of amino-1-phenyl-acetone (7) synthesis, and also eliminates the formation of five by-products of compound (3), compound (4), compound (5), compound (8) and compound (9) possibility. This can eliminate acidification→layering→extraction→basing→layering→extraction→reacidification→layering→extraction→rebasification→pointing under the conditions of different pH values reported in the literature and actual industrial production. Layer→Extraction of the complex purified crude 2-methylamino-1-phenyl-propanone (7).

The invention also provides a method for preparing ephedrine or pseudoephedrine, comprising splitting and reducing 2-methylamino-1-phenyl-1-propanone to form ephedrine or pseudoephedrine, the 2-methylamino-1 -Phenyl-1-propanone is prepared by the preparation method of the ephedrine or pseudoephedrine intermediate described in any one of the above aspects. Taking ephedrine as an example, the reaction route is as follows:

Preferably, the solvent used in the reduction process is a mixed solvent of methanol and water.

In the published papers and patent documents, the carbonyl group in the resolved product of the intermediate 2-methylamino-1-phenyl-acetone (7) is carried out from potassium borohydride or sodium borohydride in methanol or water. The reduction in methanol has the danger of direct reaction of potassium borohydride and methanol, releasing a large amount of hydrogen and generating heat, causing the reaction liquid to rapidly heat up:

KBH ₄ +CH ₃ OH→KB(OCH ₃ ) ₄ +4H ₂ ↑+heat

This brings certain security risks to large production.

When the reduction is carried out in water, the reaction is stable and safe, and the chemical yield is ideal, but the proportion of ephedrine in the product decreases, and the proportion of pseudoephedrine increases, that is, the optical purity decreases. This brings difficulties to the purification of ephedrine.

This patent finds that the above two major drawbacks can be overcome if a mixed solvent of methanol and water is used. Preferably, the volume ratio of methanol to water is (1-10): (10-1). As a further preference, the optimum volume ratio of the two is 50:50.

In the present invention, the potassium borohydride or sodium borohydride reduction reaction is carried out at a low temperature in a mixed solution of methanol and water. Preferably, the reduction reaction temperature is between -30 ° C and 15 ° C.

The present invention is directed to the following novel process and method: 2-Chloropropionyl chloride and benzene are used as starting materials to complete the Friedel-Craft reaction. The Friedel-Craft product 2-chloro-1-phenyl-acetone is directly reacted with methylamine in a sealed environment in the absence of oxygen in an aprotic solvent without purification to form 2-methylamino-1-phenyl-acetone. . This key intermediate can be used in the resolution and reduction of the next optical isomer by a simple purification treatment to obtain the desired ephedrine and pseudoephedrine.

This process no longer uses highly contaminated phosphorus trichloride, and no longer uses dangerous and expensive bromine. Moreover, the Friedel-Crafts reaction and the methylation reaction are carried out in the same solvent, saving the utility of the utility. In summary, the advantages of the present invention are apparent, providing a safe, simple, inexpensive, green ephedrine and pseudoephedrine synthesis process.

detailed description

First step reaction, preparation of 2-chloro-1-phenyl-acetone (6)

Example 1 (Excess benzene is used in the Friedel-Craft reaction and used directly as a solvent for the methylation reaction)

Add 2 liters of reaction flask to benzene (500 ml, 5.6 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, slowly within 2 hours. - Chloropropanoyl chloride (254 g, 2.0 mol) was added to the reaction flask. The reaction was continued for one hour while maintaining the reaction temperature below 10 °C. The temperature was raised to 20-30 ° C for another two hours. Gas phase analysis no longer showed the presence of 2-chloropropionyl chloride.

600 ml of ice water and 150 ml of 35% hydrochloric acid were added successively to decompose excess aluminum trichloride. The reaction solution was allowed to stand for stratification, and the upper layer of benzene was taken, washed once with water, and then allowed to stand for thorough stratification. The benzene liquid shows that the purity of the HPLC product is 98.52%, which can be directly used in the next methylation reaction.

Example 2 (toluene-substituted benzene as solvent for methylation reaction)

In a 2 liter reaction flask, benzene (350 ml, 3.94 mol) and anhydrous aluminum trichloride (300 g, 2.25 mol) were added under a nitrogen atmosphere. 2-Chloropropionyl chloride (254 g, 2.0 mol) was started to be added dropwise while stirring to 0 to 5 °C. After the completion of the dropwise addition for 30 minutes, the temperature was raised to 20-30 ° C, and the reaction was continued for three hours. The gas phase showed that 2-chloropropionyl chloride no longer remained.

600 ml of ice water and 150 ml of 35% concentrated hydrochloric acid were successively added to the reaction liquid. Stirring was continued for 15 minutes after the completion of the dropwise addition, and then the layers were allowed to stand. The upper benzene layer was washed once with water and then allowed to stand for stratification. The separated benzene layer solution distills off benzene. To about 1/3 volume, 800 ml of toluene was added to continue distillation, replacing all of the benzene. HPLC showed the content of the product (6) at 98.33%. This toluene solution can be directly reacted with the methylamine.

Example 3 (acetonitrile substituted benzene as solvent for methylation reaction)

Add 2 liters of benzene (600 ml, 6.73 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, start adding 2-chloro Propionyl chloride (254 g, 2.0 mol). After 30 minutes of addition, the temperature was raised to 20-30 ° C for three hours. The gas phase showed that 2-chloropropionyl chloride was completely consumed.

400 ml of ice water was slowly added dropwise to the reaction solution, and after stirring for 10 minutes, 150 ml of 35% concentrated hydrochloric acid was added. After the dropwise addition, the mixture was further stirred for ten minutes. Wash the upper benzene layer once, then divide Floor. The separated benzene layer is concentrated under normal pressure, and 500 ml of anhydrous acetonitrile is added to the solution while it is nearly dry, and it can be directly used for the next methylation reaction. HPLC showed a product purity of 98.02%.

Second step reaction, preparation of 2-methylamino-1-phenyl-acetone (7) and its hydrochloride (10)

Example 4 (Preparation of 2-methylamino-1-phenyl-acetone under normal pressure in a benzene solution)

90 ml of the benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) obtained in the above reaction was transferred to a 0.5 liter reaction flask under a nitrogen atmosphere. After cooling to about -20 ° C, a 20% solution of methylamine in benzene (107 ml, containing 21.4 g of methylamine, 0.69 mol) was slowly added dropwise. After the completion of the dropwise addition, the temperature was slowly raised to 0 ° C for three hours, and then the temperature was raised to 10 ° C for three hours, and the temperature was further raised to 20 ° C for eight hours. The HPLC product purity after the reaction was 98.21%.

100 ml of ice water was added to the reaction flask, and the reaction solution was controlled to dropwise add concentrated hydrochloric acid in the range of 0 to 5 ° C until pH = 2-3. The aqueous layer was separated, the aqueous layer was washed twice with dichloromethane, and then dichloromethane was evaporated, and then evaporated to dryness to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (41.2 g, Total step yield 90.0%)

Example 5 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in a benzene solution)

Under a nitrogen atmosphere, benzene (60 g, 0.77 mol) was added to a 0.5 liter pressure reaction flask, and methylamine gas (14.2 g, 0.46 mol, methylamine solution concentration 20%) was introduced while cooling to about 5 °C. Anhydrous potassium carbonate (31.6 g, 0.23 mol) was added at the same temperature, and after stirring, 90 ml of a benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) was added. After sealing the reaction flask, the temperature was slowly raised to 20-30 ° C, the pressure reading in the reaction flask was 0.05 MPa, the reaction was kept for 10 hours, and the peak purity of the HPLC product was 98.74%.

After the completion of the reaction, 80 ml of water was added, stirred, and the temperature was lowered to about 5 ° C to neutralize with 35% concentrated hydrochloric acid to pH = 1-2, and the aqueous layer was separated. The acidified aqueous layer was washed twice with dichloromethane. After distilling off the dichloromethane, the aqueous layer was evaporated to dryness to dryness to give crystals (yield (yield) of 2-methylamino-1-phenyl-acetone (42.5 g, 2

Example 6 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in an acetonitrile solution)

Under nitrogen protection, slowly introduce methylamine gas into a 0.5 liter pressure bottle pre-cooled to -20 °C The liquid methylamine (42.6 g, 1.38 mol) was collected, and 180 ml of an acetonitrile solution containing 2-chloro-1-phenyl-acetone (77.6 g, 0.46 mol) was added dropwise at the same temperature, and the closed reactor was slowly heated to 20- The reaction was carried out at 30 ° C for 6 hours, cooled to 0-5 ° C, and then acidified to pH = 1-2 by the addition of 35% concentrated hydrochloric acid.

The acetonitrile and water were concentrated under reduced pressure to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (81.48 g), which was filtered and dried and collected, and the total yield of the two steps was 90.1%.

Control reaction using aqueous solution of methylamine in proton solution

Example 7 (Methylation reaction in an aqueous solution of 40% methylamine)

An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1) and 40% methylamine (47.3 g, 1.53 mol) was added at room temperature to 118.3 g. Mix well with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 45.51%, the impurity one (RT5.68) was 4.30%, the impurity two (RT9.03) was 48.14%, and the impurity three ( RT11.64) is 2.05%.

Example 8 (Methylation of 40% aqueous solution of methylamine in the presence of sodium hydroxide)

An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1), 40% methylamine (23.7 g, 0.76 mol), 59.2 g, at room temperature It was uniformly mixed with a 30% aqueous sodium hydroxide solution (30.6 g, 0.76 mol) with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 40.51%, the impurity one (RT5.4) was 4.32%, the impurity two (RT9.0) was 44.29%, and the impurity three ( RT 11.1) is 4.90%. The impurity IV (RT12.8) was 5.10%, and the impurity five (RT24.4) was 0.88%.

The third step (split 2-Methylamino-1-phenyl-acetone (±)-7 resolution)

Example 9

Mixing 2-methylamino-1-phenyl-acetone hydrochloride (±)-10 (192 g, 0.96 mol) was carried out according to the method disclosed in the literature, and the desired (-)-7 was collected by filtration. (-)-DBTA composite salt, dried under reduced pressure under nitrogen to obtain 233.2 g of a white solid, yield 71.0%

The fourth step reaction (preparation of ephedrine (1))

Example 10

(S)-(-)-2-Methylamino-1-phenyl-acetone-DBTA complex salt (233.2 g, 0.34 mol) was placed in a reaction flask under nitrogen. A 50% by volume aqueous solution of methanol (700 ml) was added and stirred at room temperature to form a clear solution. Cool down to between -10 and -5 ° C and add potassium borohydride powder and maintain the same low temperature reaction for 30 to 60 minutes. The disappearance of the starting material by HPLC showed that the reaction mixture was evaporated to dryness, evaporated, evaporated, and evaporated. The precipitated (-)-DBTA was extracted twice with ethyl acetate. A 10 N aqueous sodium hydroxide solution was added dropwise to an acidic aqueous solution which had been cooled to 0 to 5 ° C until pH = 12. The precipitated oil was extracted three times with toluene. The combined organic phases were washed once with water and once with saturated brine. 5N hydrochloric acid was added dropwise to the toluene solution until pH = 5-6, and the mixture was further stirred for 15 minutes and then layered. The aqueous layer was separated and concentrated to dryness under reduced pressure to give ephedrine (1) hydrochloride (124.6 g, 91.1%, specific rotation -34.5).

In the examples of the present invention, all the obtained intermediates or final products can be detected by the existing structure detection method. The structural detection of the intermediate or final product obtained by the present invention is consistent with the known reported detection data.

Claims

The invention relates to a method for preparing an intermediate of ephedrine or pseudoephedrine, which comprises: using 2-chloropropionyl chloride and benzene as starting materials, and performing a Friedel-Craft reaction under Lewis acid catalysis to form 2-chloro-1 -Phenyl-1-propanone.
The method for producing an ephedrine or pseudoephedrine intermediate according to claim 1, wherein the molar ratio of the 2-chloropropionyl chloride to benzene is 1: (2 to 50).
The method for producing an ephedrine or pseudoephedrine intermediate according to claim 1, wherein benzene simultaneously serves as a reaction solvent for the Friedel-Craft reaction.
The method for preparing an ephedrine or pseudoephedrine intermediate according to any one of claims 1 to 3, further comprising the steps of:

The resulting 2-chloro-1-phenyl-1-propanone and methylamine are reacted in an aprotic solvent to give 2-methylamino-1-phenyl-1-propanone.
The method for preparing an ephedrine or pseudoephedrine intermediate according to claim 4, wherein after the completion of the Friedel-Craft reaction, the Lewis acid catalyst is removed, and the organic phase is washed and directly reacted with methylamine, and benzene is simultaneously used as a The reaction solvent of the reaction and the reaction solvent for producing 2-methylamino-1-phenyl-1-propanone.
The method for preparing an ephedrine or pseudoephedrine intermediate according to claim 4, wherein the aprotic solvent is selected from the group consisting of benzene, toluene, xylene, trimethylbenzene, C5-C12 linear alkane, cyclopentane, Cyclohexane, petroleum ether, dichloromethane, chloroform, dichloroethane, trichloroethane, dichloroethylene, trichloroethylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, hexahydrocyclohexane, acetonitrile One or more of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrole.
The method for producing an ephedrine or pseudoephedrine intermediate according to claim 4, wherein the molar ratio of 2-chloro-1-phenyl-acetone to methylamine is 1:1 to 5.
The method for preparing an ephedrine or pseudoephedrine intermediate according to claim 7, wherein the molar ratio of 2-chloro-1-phenyl-acetone to methylamine is 1: (2.5 to 3.5), and methylamine At the same time as an acid binding agent;

Alternatively, the molar ratio of the 2-chloro-1-phenyl-acetone to methylamine is 1: (1.5 to 2.5), and The base is used as an acid binding agent.
The method for preparing an ephedrine or pseudoephedrine intermediate according to claim 8, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium oxide, and oxidation. One or more of magnesium, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, a tertiary amine or a quaternary amine base.
The method for producing an ephedrine or pseudoephedrine intermediate according to claim 4, wherein the reaction pressure is 0-1 MPa.
The process for the preparation of an ephedrine or pseudoephedrine intermediate according to claim 4, wherein the reaction is carried out under conditions of no oxygen, no water or no oxygen.
A method for preparing ephedrine or pseudoephedrine, comprising: splitting and reducing 2-methylamino-1-phenyl-1-propanone to form ephedrine or pseudoephedrine, wherein the 2-methylamino-1- Phenyl-1-propanone is prepared by the method for producing an ephedrine or pseudoephedrine intermediate according to any one of claims 4 to 11.
The method for producing ephedrine or pseudoephedrine according to claim 12, wherein the solvent used in the reduction process is a mixed solvent of methanol and water.
The method for producing ephedrine or pseudoephedrine according to claim 13, wherein the volume ratio of methanol to water is (1-10): (10-1).