A chiral synthesis of a key galanthamine hydrobromide impurity, epigalanthamine hydrobromide

Abstract

The application relates to the field of new medical compounds, in particular to a chiral synthesis method of a key galanthamine hydrobromide impurity, epigalanthamine hydrobromide. The epigalanthamine hydrobromide is synthesized in one step by using an intermediate easy for industrial production as raw material. The synthesis method uses the intermediate in the existing industrial production process, has the advantages of simple steps, low reagent cost, high yield and high optical purity of the product, and greatly facilitates the further development of the impurity preparation of galanthamine and the drug analysis method of galanthamine.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of new pharmaceutical compounds, in particular to a chiral synthesis method of a key impurity of galanthamine hydrobromide, epigalanthamine hydrobromide. BACKGROUND

[0002] Galanthamine hydrobromide is a highly selective cholinesterase inhibitor, has weak anticholinesterase effect, can penetrate the blood-brain barrier, and has a strong effect on the central nervous system. It restores the blocked neuromuscular transmission and improves the paralyzed state of various peripheral neuromuscular disorders. It has a wide range of treatment, low toxicity, and is more easily tolerated by patients. It is mainly used in the treatment of post-polio syndrome, muscle atrophy, myasthenia gravis, and the like. It can also be used for pediatric cerebral palsy, traumatic sensory motor disorders, multiple neuritis, and spinal radiculitis.

[0003] Galanthamine was first marketed in the United Kingdom and Ireland after being approved by the European Union as an anti-AD drug in July 2000; in 2001, the US Food and Drug Administration approved it for the treatment of Alzheimer's disease, and it is now marketed in 25 countries. Different methods are used by various countries in formulating the pharmaceutical standards of the drug, and therefore the impurity spectrum of the drug plays an important role in the process of drug registration and raw material production. Epigalanthamine hydrobromide is the corresponding isomer of galanthamine hydrobromide, and has a clear limit standard in the pharmacopoeia of various regions. The structures of galanthamine hydrobromide and epigalanthamine hydrobromide are shown in the following figure:

[0004]

[0005] As the enantiomeric form of galanthamine hydrobromide, epigalanthamine hydrobromide needs to be positioned and structurally confirmed when galanthamine hydrobromide is registered, and this requires high-purity epigalanthamine hydrobromide; in the production process of galanthamine hydrobromide, epigalanthamine hydrobromide is used as a control for a series of analyses; in the galanthamine hydrobromide product, epigalanthamine hydrobromide is an invalid component, and its presence will reduce the drug concentration of galanthamine hydrobromide.

[0006] Epigalanthamine hydrobromide is a by-product of galanthamine hydrobromide, and the production methods of galanthamine hydrobromide are divided into plant extraction and chemical synthesis. In the plant extraction method, the extract composition is complex, and the process is complicated, which is not suitable for impurity extraction; in the chemical synthesis method, it is divided into chiral preparation method and resolution method. In the chiral preparation method, the content of epigalanthamine hydrobromide is extremely low, and it needs to be prepared by continuous preparation of hundreds of needles of preparative liquid chromatography to obtain milligram-level amount. In the resolution method, although the content of epigalanthamine hydrobromide is high, it also needs to be prepared by preparative liquid chromatography or silica gel column, which is time-consuming and high in cost.

[0007] Therefore, how to obtain the galanthamine hydrobromide more simply and effectively becomes one of the problems to be solved by the person skilled in the art. SUMMARY

[0008] The present application provides a chiral synthesis method of galanthamine hydrobromide key impurity-galanthamine hydrobromide, which uses an intermediate easy to produce in industry as raw material to synthesize the galanthamine hydrobromide by one step of chiral reductant. The synthesis method uses the intermediate in the existing industrial production process, has the advantages of simple steps, low reagent cost, high yield and high optical purity of the product, greatly facilitates the further development of the impurity preparation of galanthamine and the drug analysis method of galanthamine.

[0009] The chiral synthesis method of galanthamine hydrobromide provided by the present application is to use (-) narwedine as raw material to obtain galanthamine hydrobromide through the steps of carbonyl activation, chiral reduction and salt purification, and the specific reaction equation is as follows:

[0010]

[0011] More specifically, the steps are as follows:

[0012] (1) Carbonyl activation: (-) narwedine, aluminum trichloride and solvent are mixed and heated for activation, the mass ratio of the three is 1:0.001-0.1:1-10, the heating temperature is 70-83℃, and the activation time is 1-3 hours; the solvent is ethanol, isopropanol, tert-butyl alcohol, 3-pentanol, 2-ethylbutanol or other branched monol or polyol with less than C8;

[0013] The mass ratio of the above three is preferably 1:0.001:5; the heating temperature is preferably 82.5℃ (small reflux temperature); the solvent is preferably isopropanol; and the activation time is preferably 1 hour.

[0014] (2) Chiral reduction: under the premise of maintaining the system temperature, the reducing agent is added to the system in batches within 1-3 hours to maintain the reaction temperature, and the enantiomeric galanthamine is obtained;

[0015] More specifically, under the premise of maintaining the system temperature, the reducing agent is added to the system in batches (average to one batch every 10 minutes) within 1-3 hours; wherein the reducing agent used is aluminum isopropoxide, and the molar ratio of (-) narwedine to the reducing agent is 1:1-3; and the reaction time after the addition is completed is 1-5 hours;

[0016] Further, the molar ratio of (-) narwedine to the reducing agent is preferably 1:1.05; the addition time is preferably 1.5 hours; and the reaction time after the addition is completed is 2 hours.

[0017] (3) Purification of ecogalantamine: the reaction solution obtained in step (2) is concentrated and dried, the concentration and drying standard being that the mass of the residue is less than or equal to 1.5 times the total mass of (-) narwedine and aluminum isopropoxide; then the active substance is extracted using water and an extraction solvent; after the extraction is completed, the extraction solvent is washed with water to remove salts and dried with a drying agent to remove water to obtain an extraction phase containing the product;

[0018] The concentration and drying standard is preferably that the mass of the residue is 1.1 times the total mass of (-) narwedine and aluminum isopropoxide.

[0019] The mass of water is 1-6 times that of the reducing agent; the extraction solvent is one of ethyl acetate, butanol, dichloromethane, 1,2-dichloroethane, and toluene; the amount of extraction solvent used each time is 3-6 times the mass of (-) narwedine, and the extraction temperature is 5-50°C; the drying agent is one of anhydrous calcium chloride, molecular sieves, anhydrous sodium sulfate, and anhydrous magnesium sulfate; the amount of drying agent used is 5-30% of the total mass of the extraction solvent.

[0020] Preferably, the mass of water is 3 times that of the reducing agent; the extraction solvent is preferably ethyl acetate; the amount of extraction solvent used each time is 6 times the mass of (-) narwedine; the extraction temperature is preferably 15-30°C; the drying agent is preferably anhydrous sodium sulfate; and the amount of drying agent used is 10% of the total mass of the extraction solvent.

[0021] (4) Salting: a hydrobromic acid solution is added dropwise to the extraction phase, and after salting and precipitation, the product, hydrobromic acid ecogalantamine, is obtained by filtration and drying;

[0022] The salting temperature is 5-15°C; the amount of hydrobromic acid solution used is 1-3 times the molar amount of (-) narwedine; the solvent composition of the hydrobromic acid solution is one or a combination of more than one of water, methanol, ethanol, tetrahydrofuran, and acetonitrile, and the most preferred composition is 1 volume part of 47% hydrobromic acid aqueous solution and 3 volume parts of ethanol; the amount of hydrobromic acid solution used is 1.1 times the molar amount of (-) narwedine.

[0023] The above preparation process uses a preferred reducing agent and sets a specific reduction reflux temperature to ensure that the final product is hydrobromic acid ecogalantamine. The salting temperature is also limited to ensure that the final product is hydrobromic acid ecogalantamine. Any change in the technical solutions will result in a decrease in the purity of the final hydrobromic acid ecogalantamine.

[0024] The (-) narwedine is prepared using existing technology, and the optional preparation route is as follows:

[0025]

[0026] The specific preparation process can refer to existing technology, and the applicant will not repeat it here.

[0027] In summary, the present application adopts (-) narwedine as raw material, which is an intermediate in the production process of galanthamine hydrobromide, to synthesize the chiral drug impurity epigalanthamine hydrobromide by aluminum isopropoxide, which has the advantages of simple steps, low reagent cost, high yield, and high optical purity of the product, and the purity and content meet the requirements of drug registration and drug analysis. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0029] Figure 2 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0030] Figure 3 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0031] Figure 4 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0032] Figure 5 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0033] Figure 6 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0034] Figure 7 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard,

[0035] Figure 8 Table of peaks for the liquid chromatography positioning spectrum of galanthamine hydrobromide standard. DETAILED DESCRIPTION

[0036] The present application will be further described below in conjunction with examples, which can enable those skilled in the art to more fully understand the present application, but in no way limit the present application.

[0037] Example 1

[0038] A chiral synthesis method of a key impurity of galanthamine hydrobromide, epigalanthamine hydrobromide, is as follows:

[0039] Step one: 28.5g of (-) narwedine, 28.5mg of aluminum chloride and 142.5g of isopropyl alcohol are put into a 500ml three-necked reaction bottle, and the temperature is raised to a small reflux temperature of 82.5℃; the small reflux temperature is maintained for 1 hour;

[0040] Step two: 21.5g of isopropyl aluminum is added to the above reaction system in batches, and the addition time is controlled for 1.5 hours; after the addition is completed, 82.5℃ is maintained for 2 hours;

[0041] Step three: the reaction solution in step two was reduced pressure distillation, concentrated to 55 g; to the solid pot residue was added water 64.5 g, ethyl acetate 171 g, stirring extraction at 20℃; liquid separation, the water phase was separated, ethyl acetate 171 g was extracted again; the combined ethyl acetate phase was added anhydrous sodium sulfate 34.2 g, stirred at 20℃ for 3 hours;

[0042] Step four: after the ethyl acetate phase was filtered, it was stirred at a lower temperature, the temperature was controlled at about 10℃, a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3) was added dropwise, and the amount of hydrobromic acid solution was 1.1 times the molar amount of (-) navelbine; after stirring for 2 hours, the product 34.9 g was obtained by filtering and drying.

[0043] The purity of hydrobromic acid tacrin was 99.15% detected by high performance liquid chromatograph, and the liquid phase detection data were as follows: Figure 4 , Figure 4 The main peak position was 7.723 min, which was consistent with the position of the hydrobromic acid tacrin reference substance in Figure 3 , indicating that the hydrobromic acid tacrin was successfully prepared in this example.

[0044] Example 2

[0045] A chiral synthesis method of a key impurity of hydrobromic acid galanthamine, hydrobromic acid tacrin, was as follows:

[0046] Step one: (-) navelbine 28.5 g, 28.5 mg aluminum trichloride and isopropyl alcohol 142.5 g were put into a 500 ml three-necked reaction bottle, and the temperature was raised to a small reflux temperature of 82.5℃; the small reflux temperature was maintained for 1 hour;

[0047] Step two: 17.2 g of isopropyl aluminum was added to the above reaction system in batches, and the addition time was controlled within 1.5 hours; after the addition was completed, the temperature was maintained at 82.5℃ for 2 hours;

[0048] Step three: the reaction solution in step two was reduced pressure distillation, concentrated to 48.6 g; to the solid pot residue was added water 51.6 g, ethyl acetate 171 g, stirring extraction at 20℃; liquid separation, the water phase was separated, ethyl acetate 171 g was extracted again; the combined ethyl acetate phase was added anhydrous sodium sulfate 34.2 g, stirred at 20℃ for 3 hours;

[0049] Step four: after the ethyl acetate phase was filtered, it was stirred at a lower temperature, the temperature was controlled at about 10℃, a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3) was added dropwise, and the amount of hydrobromic acid solution was 1.1 times the molar amount of (-) navelbine; after stirring for 2 hours, the product 35.1 g was obtained by filtering and drying.

[0050] The purity of hydrobromic acid tacrin was 81.57% detected by high performance liquid chromatograph, and the liquid phase detection data were as follows: Figure 5, remaining a large amount of (-) narwedine unreacted, indicating that reducing the ratio of reducing agent is not conducive to the complete reduction of the substrate and has a great impact on the purity of the product.

[0051] Example 3

[0052] A chiral synthesis method of a key impurity of galanthamine hydrobromide, galanthamine hydrobromide, is as follows:

[0053] Step one: 28.5g of (-) narwedine, 28.5mg of aluminum chloride and 142.5g of isopropyl alcohol were put into a 500ml three-necked reaction bottle, and the temperature was raised to a small reflux temperature of 82.5℃; keep the small reflux temperature for 1 hour;

[0054] Step two: 21.5g of aluminum isopropoxide was added to the above reaction system in batches, and the addition time was controlled for 1.5 hours; after adding, 82.5℃ was kept for 1 hour;

[0055] Step three: The reaction liquid in step two was distilled under reduced pressure, concentrated to 55g; 64.5g of water and 171g of ethyl acetate were added to the solid kettle residue, and stirred at 20℃; the aqueous phase was separated, and 171g of ethyl acetate was extracted again; the combined ethyl acetate phase was added with 34.2g of anhydrous sodium sulfate, and stirred at 20℃ for 3 hours;

[0056] Step four: After the ethyl acetate phase was filtered and cooled, 47% hydrobromic acid and ethanol mixed solution (volume ratio 1:3) was added dropwise, and the amount of hydrobromic acid solution was 1.1 times of the molar amount of (-) narwedine; keep stirring for 2 hours, then filter and dry to obtain the product 35.0g;

[0057] The purity of galanthamine hydrobromide was 64.29% by high performance liquid chromatography, and the liquid phase detection data were as follows: Figure 6 , remaining a large amount of (-) narwedine unreacted, indicating that reducing the ratio of reducing agent is not conducive to the complete reduction of the substrate and has a great impact on the purity of the product.

[0058] Example 4

[0059] A chiral synthesis method of a key impurity of galanthamine hydrobromide, galanthamine hydrobromide, is as follows:

[0060] Step one: 28.5g of (-) narwedine and 142.5g of isopropyl alcohol were put into a 500ml three-necked reaction bottle;

[0061] Step two: 21.5g of aluminum isopropoxide was added to the above reaction system in batches, and the addition time was controlled for 1.5 hours; after adding, 82.5℃ was kept for 2 hours;

[0062] Step three: the reaction solution in step two was distilled under reduced pressure, concentrated to 55 g; water 64.5 g, ethyl acetate 171 g was added to the solid pot residue, stirring extraction at 20℃; liquid separation, the water phase was separated, ethyl acetate 171 g was extracted again; ethyl acetate phase was combined and anhydrous sodium sulfate 34.2 g was added, stirring drying at 20℃ for 3 hours;

[0063] Step four: after the ethyl acetate phase was filtered, it was stirred at low temperature, the temperature was controlled at about 10℃, and a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3) was added dropwise, and the amount of hydrobromic acid solution was 1.1 times the molar amount of (-)navidine; after stirring for 2 hours, the product 35.0 g was obtained by filtering and drying.

[0064] The purity of hydrobromic acid tabletanisamine was 46.72% detected by high performance liquid chromatograph, and the liquid phase detection data are shown in Figure 7 , and the remaining was hydrobromic acid galanthamine peak, the ratio of the two was close to 1:1, indicating that the lack of carbonyl activation step could not prepare high optical purity of hydrobromic acid tabletanisamine.

[0065] Comparative example 1

[0066] A chiral synthesis method of a key impurity of hydrobromic acid galanthamine-hydrobromic acid tabletanisamine, the specific steps are as follows:

[0067] Step one: (-)navidine 28.5 g and tetrahydrofuran 142.5 g were put into a 500 ml three-necked reaction bottle, and stirring was carried out to reduce the temperature to 0-5℃; the temperature was kept for 1 hour;

[0068] Step two: 4 g of sodium borohydride was added to the reaction system in batches, and the addition time was controlled within 1.5 hours; after the addition was completed, the temperature was kept at 0-5℃ for 2 hours; then the temperature was restored to room temperature and stirred for 6 hours;

[0069] Step three: the reaction solution in step two was distilled under reduced pressure, concentrated to 35.8 g; water 12 g, ethyl acetate 171 g was added to the solid pot residue, stirring extraction at 20℃; liquid separation, the water phase was separated, ethyl acetate 171 g was extracted again; ethyl acetate phase was combined and anhydrous sodium sulfate 34.2 g was added, stirring drying at 20℃ for 3 hours;

[0070] Step four: after the ethyl acetate phase was filtered, it was stirred at low temperature, the temperature was controlled at about 10℃, and a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3) was added dropwise; after stirring for 2 hours, the product 34.7 g was obtained by filtering and drying, and the spectrum of the product is shown in Figure 8 , indicating that the product contains hydrobromic acid galanthamine, hydrobromic acid force clara min, other unknown substances, the product is complex, sodium borohydride as a reducing agent has strong reducing ability, poor chiral selectivity, so pure hydrobromic acid galanthamine cannot be obtained.

[0071] The above merely describes the preferred embodiments of the present application and is not used to limit the present application, and any equivalent replacement, modification, etc. made by those skilled in the art within the spirit and principle of the present application without any creative labor should be included in the protection scope of the present application.

Claims

1. A chiral synthesis of a key galantamine hydrobromide impurity - galanthamine hydrobromide, characterized by, With (-) narwedine as raw material, the hydrobromic acid table granthanmin is obtained by the steps of carbonyl activation, chiral reduction and purification of salt through aluminum chloride, and the specific reaction equation is as follows: 。 2. The chiral synthesis of the hydrobromide of eptastigmine according to claim 1, characterized by: The specific steps are as follows: (1) Carbonyl activation: (-) narwedine, aluminum chloride and solvent are blended and heated for activation, the mass ratio of the three is 1:0.001-0.1:1-10, the heating temperature is 70-83℃, and the activation time is 1-3 hours; (2) Chiral reduction: under the premise of maintaining the temperature of the system, the reducing agent is added to the system in batches within 1-3 hours to maintain the reaction temperature, and the enantiomeric table granthanmin is obtained; (3) Purification of table granthanmin: the reaction liquid obtained in step (2) is concentrated and dried, the standard of concentration and drying is that the mass of the residue is less than or equal to 1.5 times the total mass of (-) narwedine and aluminum isopropoxide; Then the active substance is extracted with water and extractant; After the extraction is completed, the extractant is washed with water to remove salt, dried with drying agent to remove water, and then the extract phase containing the product is obtained; (4) Salting: add hydrobromic acid solution to the extract phase, filter and dry after salting to obtain the product hydrobromic acid table granthanmin.

3. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 2, characterized by: In step (1), the solvent is ethanol, isopropanol, tert-butyl alcohol, 3-pentanol, 2-ethylbutanol or other branched monol or polyol below C8; The mass ratio of (-) narwedine, aluminum chloride and solvent is 1:0.001:5; The heating temperature is 82.5℃; The activation time is 1 hour.

4. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 2, characterized by: In step (2), the reducing agent is added to the system in batches, with an average of one batch every 10 minutes; The reducing agent used is aluminum isopropoxide, and the molar ratio of (-) narwedine to reducing agent is 1:1-3; After the addition is completed, the reaction time is 1-5 hours.

5. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 4, characterized by: In step (2), the molar ratio of (-) narwedine to reducing agent is 1:1.05; The addition time is 1.5 hours; After the addition is completed, the reaction time is 2 hours.

6. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 2, characterized by: In step (3), the standard of concentration and drying is that the mass of the residue is 1.1 times the total mass of (-) narwedine and aluminum isopropoxide; The mass of water is 1-6 times that of the reducing agent; The extraction solvent is one of ethyl acetate, butanol, dichloromethane, 1,2-dichloroethane and toluene; The extraction solvent is used in an amount of 3-6 times the mass of (-) narwedine each time, and the extraction temperature is 5-50℃; The drying agent is one of anhydrous calcium chloride, molecular sieve, anhydrous sodium sulfate and anhydrous magnesium sulfate; The amount of drying agent is 5%-30% of the total mass of the extraction solvent.

7. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 6, characterized by: In step (3), the mass of water is 3-6 times that of the reducing agent; The extraction solvent is ethyl acetate; The extraction solvent is used in an amount of 6 times the mass of (-) narwedine each time; The extraction temperature is 15-30℃; The drying agent is anhydrous sodium sulfate; The amount of drying agent is 10% of the total mass of the extraction solvent.

8. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 2, characterized by: In step (4), the salting temperature is 5-15℃; The amount of hydrobromic acid solution is 1-3 times the molar amount of (-) narwedine; The solvent composition of the hydrobromic acid solution is one or a combination of more than one of water, methanol, ethanol, tetrahydrofuran and acetonitrile.

9. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 8, characterized by: The amount of hydrobromic acid solution is 1.1 times the molar amount of (-) narwedine.

10. The chiral synthesis of the hydrobromide salt of tabletanhsmin according to claim 8, characterized by: In step (4), the solvent composition of the hydrobromic acid solution is a combination of 47% hydrobromic acid aqueous solution 1 volume part and ethanol 3 volume parts.

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