WO2017211129A1 - Procédé de production d'éphédrine ou de pseudoéphédrine et d'intermédiaire d'éphédrine ou de pseudoéphédrine - Google Patents

Procédé de production d'éphédrine ou de pseudoéphédrine et d'intermédiaire d'éphédrine ou de pseudoéphédrine Download PDF

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Publication number
WO2017211129A1
WO2017211129A1 PCT/CN2017/080841 CN2017080841W WO2017211129A1 WO 2017211129 A1 WO2017211129 A1 WO 2017211129A1 CN 2017080841 W CN2017080841 W CN 2017080841W WO 2017211129 A1 WO2017211129 A1 WO 2017211129A1
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ephedrine
pseudoephedrine
reaction
phenyl
methylamine
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PCT/CN2017/080841
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English (en)
Chinese (zh)
Inventor
王哲清
葛萌芽
叶增芳
舒理建
曾亮荣
方梅芬
孙云雷
张柯华
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浙江普洛康裕制药有限公司
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Publication of WO2017211129A1 publication Critical patent/WO2017211129A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • 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.
  • Ephedra is a wild plant that has been used for sweating and asthma in Chinese medicine for thousands of years.
  • Japanese scholar Chang Changyi first separated the mixture of active ingredients from the plant of Ephedra, and its main component was ephedrine.
  • Merck Pharmaceuticals isolated pure ephedrine and pseudoephedrine from European ephedra plants.
  • Brewster et al. determined the absolute configuration of the two, as shown in the following equation:
  • 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.
  • the above synthetic process has the following defects, which cannot meet the technical requirements, safety requirements and environmental protection requirements of modern industrial production:
  • phosphorous acid is formed in the first step reaction.
  • the presence of large amounts of phosphorus-containing wastewater has created environmental pressures.
  • 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.
  • 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.
  • bromine takes up 33% of the cost of raw materials. This does not include the complicated operation of purifying and removing by-products.
  • 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 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.
  • 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.
  • the substitution reaction can be carried out using an aqueous solution of methylamine and a strong ⁇ -bromine atom, but another external cause which is almost incapable of reacting with the slow-reactive ⁇ -chloride atom is the hydration effect of the methylamine molecule.
  • 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 ⁇ -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.
  • 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.
  • 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 ⁇ -halogenation reaction into a one-step reaction.
  • 2-chloropropionyl chloride Compound 10
  • 2-chloro-1-phenyl-1-propanone Compound 6
  • the reaction process is as follows Show:
  • benzene is preferably used as a reaction solvent for the Friedel-Craft reaction.
  • 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".
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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:
  • 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.
  • 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.
  • 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 ⁇ -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).
  • 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.
  • 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.
  • 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).
  • 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;
  • 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.
  • a hydrogencarbonate such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate or carbonic acid.
  • sodium hydrogen, potassium hydrogencarbonate, calcium oxide, magnesium oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, a tertiary amine or a quaternary ammonium base is sodium hydrogen, potassium hydrogencarbonate, calcium oxide, magnesium oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, a tertiary amine or a quaternary ammonium base.
  • 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.
  • the molar ratio of the 2-chloro-1-phenyl-acetone to methylamine is preferably 1: (1.5 to 2.5).
  • the above reaction can be carried out under normal pressure or under pressure.
  • 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.
  • 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:
  • the solvent used in the reduction process is a mixed solvent of methanol and water.
  • 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:
  • the above two major drawbacks can be overcome if a mixed solvent of methanol and water is used.
  • the volume ratio of methanol to water is (1-10): (10-1).
  • the optimum volume ratio of the two is 50:50.
  • the potassium borohydride or sodium borohydride reduction reaction is carried out at a low temperature in a mixed solution of methanol and water.
  • 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.
  • Example 1 Excess benzene is used in the Friedel-Craft reaction and used directly as a solvent for the methylation reaction.
  • 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.
  • 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%.
  • Example 8 (Methylation of 40% aqueous solution of methylamine in the presence of sodium hydroxide)
  • the third step split 2-Methylamino-1-phenyl-acetone ( ⁇ )-7 resolution
  • 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.

Abstract

L'invention concerne un procédé de production d'un intermédiaire d'éphédrine ou de pseudoéphédrine, consistant à : utiliser du chlorure de 2-chloropropionyle et du benzène comme matières premières de départ et effectuer une réaction de Friedel-Crafts à l'aide d'un catalyseur acide de Lewis pour générer de la 2-chloro-1-phényl-1-propanone ; et faire réagir la 2-chloro-1-phényl-1-propanone produite et de la méthylamine dans un solvant aprotique pour produire de la 2-méthylamino-1-phényl-1-propanone. L'invention concerne en outre un procédé de production d'éphédrine ou de pseudoéphédrine. Le procédé n'utilise pas le trichlorure de phosphore hautement polluant et n'utilise pas le brome extrêmement dangereux et coûteux. La réaction de Friedel-Crafts et la réaction d'amination sont réalisées dans une solution unique, ce qui réduit les coûts d'infrastructure. L'invention permet ainsi d'obtenir un procédé sûr, simple, peu coûteux et écologique de synthèse d'éphédrine et de pseudoéphédrine.
PCT/CN2017/080841 2016-06-07 2017-04-18 Procédé de production d'éphédrine ou de pseudoéphédrine et d'intermédiaire d'éphédrine ou de pseudoéphédrine WO2017211129A1 (fr)

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CN201610396725.6A CN106008183B (zh) 2016-06-07 2016-06-07 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法
CN201610396725.6 2016-06-07

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CN106008183B (zh) * 2016-06-07 2019-05-07 浙江普洛康裕制药有限公司 麻黄碱或伪麻黄碱及麻黄碱或伪麻黄碱中间体的制备方法
CN112645829B (zh) * 2020-12-25 2022-10-21 浙江普洛康裕制药有限公司 麻黄碱关键中间体(s)-2-甲胺基-1-苯基-1-丙酮的手性合成方法
CN112939793B (zh) * 2021-02-03 2022-07-08 浙江普洛康裕制药有限公司 麻黄碱和伪麻黄碱工业生产过程中母液中活性成分的回收利用方法

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GB1423911A (en) * 1972-03-16 1976-02-04 Monsanto Co Production of optically active alcohols
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