Chiral synthesis method of key impurity-epigalanthamine hydrobromide of galanthamine hydrobromide

Abstract

The invention relates to the field of novel medical compounds, in particular to a chiral synthesis method of epigalanthamine hydrobromide which is a key impurity of galanthamine hydrobromide. An intermediate easy for industrial production is used as a raw material, and epigalanthamine hydrobromide is synthesized in one step through a chiral reducing agent. The synthesis method utilizes intermediates in the existing industrial production process, has the advantages of simple steps, low reagent cost, high yield, high optical purity of the product and the like, and greatly facilitates preparation of impurities of galanthamine and further development of a pharmaceutical analysis method of galanthamine.

Description

Technical Field

[0001] The invention relates to the field of new pharmaceutical compounds, and in particular to a chiral synthesis method of epigalanthamine hydrobromide, a key impurity of galanthamine hydrobromide. Background Art

[0002] Galantamine hydrobromide is a highly selective cholinesterase inhibitor with a weak anticholinesterase effect. It can penetrate the blood-brain barrier, so it has a strong effect on the central nervous system. It can restore the obstructed neuromuscular conduction and improve the paralysis state of various peripheral neuromuscular disorders. It has a wide range of treatment, low toxicity, and is easier for patients to tolerate. It is mainly used clinically to treat sequelae of poliomyelitis (poliomyelitis), muscle atrophy and myasthenia gravis. It can also be used for children's cerebral palsy, traumatic sensory motor disorders, multiple neuritis and radiculitis.

[0003] Galantamine was first marketed in the UK and Ireland in July 2000 after being approved by the European Union as an anti-AD drug. In 2001, the North American Food and Drug Administration approved it for the treatment of Alzheimer's disease, and it is now available in 25 countries. Different countries have different methods for formulating pharmacopoeia standards for this drug, so the drug impurity spectrum plays an important role in drug registration and raw material production. Epigalantamine hydrobromide is the corresponding isomer of galantamine hydrobromide, and there are clear restriction standards in the pharmacopoeias of various regions. The structures of galanthamine hydrobromide and epigalanthamine hydrobromide are shown in the figure below:

[0004]

[0005] Epigalanthamine hydrobromide is the enantiomer of galanthamine hydrobromide. When galanthamine hydrobromide is registered, it is necessary to locate and confirm its structure, which requires high-purity epigalanthamine hydrobromide. In the production process of galanthamine hydrobromide, epigalanthamine hydrobromide needs to be used as a reference substance for a series of analyses. In galanthamine hydrobromide products, epigalanthamine hydrobromide is an ineffective ingredient, 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, the process is cumbersome, and it is not suitable for the extraction of impurities; in the chemical synthesis method, it is divided into chiral preparation method and splitting method. The content of epigalanthamine hydrobromide in the chiral preparation method is extremely low, and it requires continuous preparation of hundreds of injections of preparative liquid phase to produce milligram-level quantities. Although the content of epigalanthamine hydrobromide in the splitting method is high, it also requires preparative liquid phase or silica gel column for preparation, which is time-consuming and costly.

[0007] Therefore, how to obtain epigalantamine hydrobromide more simply and effectively has become one of the problems to be solved urgently by those skilled in the art. Summary of the invention

[0008] The present invention aims at many problems existing in the prior art, and provides a chiral synthesis method of epigalanthamine hydrobromide, a key impurity of galanthamine hydrobromide, by using an intermediate that is easy to produce industrially as a raw material, and synthesizing epigalanthamine hydrobromide in one step through a chiral reducing agent. The synthesis method utilizes the intermediate in the existing industrial production process, has the advantages of simple steps, low reagent cost, high yield, and high product optical purity, and greatly facilitates the preparation of galanthamine impurities and the further development of galanthamine drug analysis methods.

[0009] The chiral synthesis method of epigalantamine hydrobromide of the present invention uses (-) navidine as a raw material, and obtains epigalantamine hydrobromide through carbonyl activation, chiral reduction, and purification and salt formation steps. The specific reaction equation is as follows:

[0010]

[0011] The more specific steps are as follows:

[0012] (1) Carbonyl activation: (-) Navidin, aluminum chloride 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-butanol, 3-pentanol, 2-ethylbutanol or other branched monoalcohols or polyols below C8;

[0013] The mass ratio of the above three is preferably 1:0.001:5; the heating temperature is preferably 82.5°C (minimum 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, a reducing agent is added to the system in batches within 1-3 hours, and the reaction temperature is maintained to obtain enantiomeric epigalanthamine;

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

[0016] Furthermore, the molar ratio of (-) narvidine 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 epigalanthamine: The reaction solution obtained in step (2) is concentrated and dried, and 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 (-) navidine and aluminum isopropoxide; then the active substance is extracted using water and an extractant; after the extraction is completed, the extractant is washed with water to remove salt and dried with a desiccant to remove moisture to obtain an extract phase containing the product;

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

[0019] The mass of water is 1-6 times of the reducing agent; the extraction solvent is one of ethyl acetate, butanol, dichloromethane, 1,2-dichloroethane and toluene; the amount of the extraction solvent used each time is 3-6 times the mass of (-) navidin, and the extraction temperature is 5°C-50°C; the desiccant is one of anhydrous calcium chloride, molecular sieve, anhydrous sodium sulfate and anhydrous magnesium sulfate; the amount of the desiccant 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 the extraction solvent used each time is 6 times the mass of (-)navitin; the extraction temperature is preferably 15°C-30°C; the desiccant is preferably anhydrous sodium sulfate; and the amount of the desiccant is 10% of the total mass of the extraction solvent.

[0021] (4) Salt formation: add hydrobromic acid solution dropwise to the extract phase, filter and dry after the salt is precipitated to obtain the product epigalanthamine hydrobromide;

[0022] The above-mentioned salt formation temperature is 5°C to 15°C; the amount of hydrobromic acid solution used is 1-3 times the molar amount of (-) navidin; the solvent composition of the hydrobromic acid solution is one or more combinations of water, methanol, ethanol, tetrahydrofuran, and acetonitrile, and the most preferred composition is 1 volume part 47% hydrobromic acid aqueous solution and 3 volume parts ethanol; the amount of hydrobromic acid solution used is 1.1 times the molar amount of (-) navidin;

[0023] The above preparation process uses a preferred reducing agent and sets a specific reduction reflux temperature to ensure that epigalanthamine hydrobromide is finally obtained. The corresponding salt formation temperature is limited during salt formation to ensure that the final configuration is epigalanthamine hydrobromide. Any change in the technical scheme will result in a deterioration in the purity of the finally obtained epigalanthamine hydrobromide.

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

[0025]

[0026] The specific preparation process can be referred to the prior art, and the applicant will not elaborate on it.

[0027] In summary, the present invention adopts the intermediate (-) navidine in the production process of galanthamine hydrobromide as a raw material, and synthesizes the drug impurity epigalanthamine hydrobromide through aluminum isopropoxide chirality, which has the advantages of simple steps, low reagent cost, high yield and high product optical purity, and the purity and content meet the requirements for drug registration and drug analysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the liquid chromatography positioning spectrum and peak table of (-) cervidine standard.

[0029] Figure 2 It is the liquid chromatography positioning spectrum and peak table of galanthamine hydrobromide standard.

[0030] Figure 3 This is the liquid chromatography positioning spectrum and peak table of galanthamine hydrobromide standard.

[0031] Figure 4 The liquid phase spectrum and peak table of the product in Example 1 are as follows:

[0032] Figure 5 The liquid phase spectrum and peak table of the product in Example 2 are as follows:

[0033] Figure 6 The liquid phase spectrum and peak table of the product in Example 3 are as follows:

[0034] Figure 7 The liquid phase spectrum and peak table of the product in Example 4 are as follows:

[0035] Figure 8 It is the liquid phase spectrum and peak table of the product in Comparative Example 1. DETAILED DESCRIPTION

[0036] The present invention is further described below in conjunction with the embodiments, which can enable those skilled in the art to more fully understand the present invention, but does not limit the present invention in any way.

[0037] Example 1

[0038] A chiral synthesis method of galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, the specific steps are as follows:

[0039] Step 1: (-) 28.5 g of narvidine, 28.5 mg of aluminum chloride and 142.5 g of isopropanol were placed in a 500 ml three-necked reaction bottle, and the temperature was raised to a small reflux temperature of 82.5°C; the small reflux temperature was maintained for 1 hour;

[0040] Step 2: 21.5 g of aluminum isopropoxide was added to the above reaction system in batches, and the addition time was controlled within 1.5 hours; after the addition, the mixture was kept at 82.5° C. for 2 hours;

[0041] Step 3: The reaction solution in step 2 was distilled under reduced pressure and concentrated to 55 g; 64.5 g of water and 171 g of ethyl acetate were added to the solid kettle residue, and the mixture was stirred and extracted at 20°C; the liquid was separated, the water phase was separated, and 171 g of ethyl acetate was extracted again; 34.2 g of anhydrous sodium sulfate was added to the ethyl acetate phase, and the mixture was stirred and dried at 20°C for 3 hours;

[0042] Step 4: After filtering the ethyl acetate phase, cool and stir, control the temperature at about 10°C, add dropwise a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3), and the amount of hydrobromic acid solution is 1.1 times the molar amount of (-) cervidine; keep warm and stir for 2 hours, then filter and dry to obtain 34.9 g of the product.

[0043] The purity of epigalantamine hydrobromide was 99.15% as detected by high performance liquid chromatography. Figure 4 , Figure 4 The main peak position is 7.723min, which is Figure 3 The position of epigalantamine hydrobromide reference substance is consistent, indicating that epigalantamine hydrobromide is successfully prepared in this example.

[0044] Example 2

[0045] A chiral synthesis method of galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, the specific steps are as follows:

[0046] Step 1: (-) 28.5 g of narvidine, 28.5 mg of aluminum chloride and 142.5 g of isopropanol were placed in a 500 ml three-necked reaction bottle, and the temperature was raised to a small reflux temperature of 82.5°C; the small reflux temperature was maintained for 1 hour;

[0047] Step 2: 17.2 g of aluminum isopropoxide was added to the above reaction system in batches, and the addition time was controlled within 1.5 hours; after the addition, the mixture was kept at 82.5° C. for 2 hours;

[0048] Step 3: The reaction solution in step 2 was distilled under reduced pressure and concentrated to 48.6 g; 51.6 g of water and 171 g of ethyl acetate were added to the solid kettle residue, and the mixture was stirred and extracted at 20°C; the liquid was separated, the water phase was separated, and 171 g of ethyl acetate was used for extraction again; 34.2 g of anhydrous sodium sulfate was added to the ethyl acetate phase, and the mixture was stirred and dried at 20°C for 3 hours;

[0049] Step 4: After filtering the ethyl acetate phase, cool and stir, control the temperature at about 10°C, add dropwise a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3), and the amount of hydrobromic acid solution is 1.1 times the molar amount of (-) cervidine; keep warm and stir for 2 hours, then filter and dry to obtain 35.1g of the product;

[0050] The purity of epigalantamine hydrobromide was 81.57% as detected by high performance liquid chromatography. Figure 5, a large amount of (-) navidin remained unreacted, indicating that reducing the reducing agent ratio 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 galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, the specific steps are as follows:

[0053] Step 1: (-) 28.5 g of narvidine, 28.5 mg of aluminum chloride and 142.5 g of isopropanol were placed in a 500 ml three-necked reaction bottle, and the temperature was raised to a small reflux temperature of 82.5°C; the small reflux temperature was maintained for 1 hour;

[0054] Step 2: 21.5 g of aluminum isopropoxide 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 reaction was kept at 82.5° C. for 1 hour;

[0055] Step 3: The reaction solution in step 2 was distilled under reduced pressure and concentrated to 55 g; 64.5 g of water and 171 g of ethyl acetate were added to the solid kettle residue, and the mixture was stirred and extracted at 20°C; the liquid was separated, the water phase was separated, and 171 g of ethyl acetate was extracted again; 34.2 g of anhydrous sodium sulfate was added to the ethyl acetate phase, and the mixture was stirred and dried at 20°C for 3 hours;

[0056] Step 4: After filtering the ethyl acetate phase, cool and stir, control the temperature at about 10°C, add dropwise a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3), and the amount of hydrobromic acid solution is 1.1 times the molar amount of (-) cervidine; keep warm and stir for 2 hours, then filter and dry to obtain 35.0 g of the product;

[0057] The purity of epigalantamine hydrobromide was 64.29% as detected by high performance liquid chromatography. Figure 6 , a large amount of (-) ceravidin remained unreacted, indicating that shortening the insulation reaction time 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 galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, the specific steps are as follows:

[0060] Step 1: (-) 28.5 g of narvidine and 142.5 g of isopropanol were added into a 500 ml three-necked reaction bottle;

[0061] Step 2: 21.5 g of aluminum isopropoxide was added to the above reaction system in batches, and the addition time was controlled within 1.5 hours; after the addition, the mixture was kept at 82.5° C. for 2 hours;

[0062] Step 3: The reaction solution in step 2 was distilled under reduced pressure and concentrated to 55 g; 64.5 g of water and 171 g of ethyl acetate were added to the solid kettle residue, and the mixture was stirred and extracted at 20°C; the liquid was separated, the water phase was separated, and 171 g of ethyl acetate was extracted again; 34.2 g of anhydrous sodium sulfate was added to the ethyl acetate phase, and the mixture was stirred and dried at 20°C for 3 hours;

[0063] Step 4: After filtering the ethyl acetate phase, cool and stir, control the temperature at about 10°C, add dropwise a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3), and the amount of hydrobromic acid solution is 1.1 times the molar amount of (-) cervidine; keep warm and stir for 2 hours, then filter and dry to obtain 35.0 g of the product.

[0064] The purity of epigalantamine hydrobromide was 46.72% as detected by high performance liquid chromatography. Figure 7 , the rest is galanthamine hydrobromide peak, and the ratio of the two is close to 1:1, indicating that the lack of carbonyl activation step cannot prepare high optical purity epigalanthamine hydrobromide.

[0065] Comparative Example 1

[0066] A chiral synthesis method of galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, the specific steps are as follows:

[0067] Step 1: (-) 28.5 g of cervidine and 142.5 g of tetrahydrofuran were placed in a 500 ml three-necked reaction bottle, stirred and cooled to 0°C-5°C; kept warm and stirred for 1 hour;

[0068] Step 2: 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, the temperature was kept at 0°C-5°C for 2 hours; then the temperature was returned to room temperature and stirred for 6 hours;

[0069] Step 3: The reaction solution in step 2 was distilled under reduced pressure and concentrated to 35.8 g; 12 g of water and 171 g of ethyl acetate were added to the solid kettle residue, and the mixture was stirred and extracted at 20°C; the liquid was separated, the water phase was separated, and 171 g of ethyl acetate was extracted again; 34.2 g of anhydrous sodium sulfate was added to the ethyl acetate phase, and the mixture was stirred and dried at 20°C for 3 hours;

[0070] Step 4: After filtering the ethyl acetate phase, cool and stir, control the temperature at about 10°C, add a mixed solution of 47% hydrobromic acid and ethanol (volume ratio 1:3) dropwise; keep warm and stir for 2 hours, filter and dry to obtain 34.7g of the product. The spectrum of the product is as follows Figure 8 As shown, the product contains galanthamine hydrobromide, licramine hydrobromide, and other unknown substances. The product is complex. Sodium borohydride is used as a reducing agent with strong reducing ability and poor chiral selectivity, so pure galanthamine hydrobromide cannot be obtained.

[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any equivalent substitutions, modifications, etc. made by technicians in this field without any creative work within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A chiral synthesis method of galanthamine hydrobromide key impurity-epigalanthamine hydrobromide, characterized in that: Using (-) navidine as a raw material, epigalantamine hydrobromide is obtained through carbonyl activation, chiral reduction, purification and salt formation steps. The specific reaction equation is as follows:

2. The chiral synthesis method of epigalantamine hydrobromide according to claim 1, characterized in that: The specific steps are as follows: (1) Carbonyl activation: (-) Navidine, aluminum chloride 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°C-83°C, and the activation time is 1-3 hours; (2) Chiral reduction: Under the premise of maintaining the system temperature, a reducing agent is added to the system in batches within 1-3 hours, and the reaction temperature is maintained to obtain enantiomeric epigalanthamine; (3) Purification of epigalantamine: The reaction solution obtained in step (2) is concentrated and dried, wherein the mass of the residue is less than or equal to 1.5 times the total mass of (-) navidine and aluminum isopropoxide; and then the active substance is extracted using water and an extractant; After the extraction is completed, the extractant is washed with water to remove salt, and the desiccant is dried to remove water to obtain an extract phase containing the product; (4) Salt formation: hydrobromic acid solution is added dropwise to the extract phase, and the salt is precipitated and filtered and dried to obtain the product epigalanthamine hydrobromide.

3. The chiral synthesis method of epigalantamine hydrobromide according to claim 2, characterized in that: In step (1), the solvent is ethanol, isopropanol, tert-butanol, 3-pentanol, 2-ethylbutanol or other branched monoalcohols or polyols with a carbon number below 8; the mass ratio of (-)navidine, aluminum chloride and the solvent is 1:0.001:5; the heating temperature is 82.5° C.; and the activation time is 1 hour.

4. The chiral synthesis method of epigalantamine hydrobromide according to claim 2, characterized in that: In step (2), the reducing agent is added to the system in batches every 10 minutes; the reducing agent used is aluminum isopropoxide, and the molar ratio of (-) narvidine to the reducing agent is 1:1-3; the reaction time after the addition is completed is 1-5 hours.

5. The chiral synthesis method of epigalantamine hydrobromide according to claim 4, characterized in that: In step (2), the molar ratio of (-) narvidine to the reducing agent is 1:1.05; the addition time is 1.5 hours; and the reaction time after the addition is completed is 2 hours.

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

7. The chiral synthesis method of epigalantamine hydrobromide according to claim 6, characterized in that: In step (3), the mass of water is 3-6 times that of the reducing agent; the extraction solvent is ethyl acetate; the amount of the extraction solvent used each time is 6 times the mass of (-)navitin; the extraction temperature is 15°C-30°C; the desiccant is anhydrous sodium sulfate; and the amount of the desiccant is 10% of the total mass of the extraction solvent.

8. The chiral synthesis method of epigalantamine hydrobromide according to claim 2, characterized in that: In step (4), the salt formation temperature is 5°C to 15°C; the amount of hydrobromic acid solution used is 1-3 times the molar amount of (-) navidin; the solvent composition of the hydrobromic acid solution is one or more combinations of water, methanol, ethanol, tetrahydrofuran, and acetonitrile; the amount of hydrobromic acid solution used is 1.1 times the molar amount of (-) navidin.

9. The chiral synthesis method of epigalantamine hydrobromide according to claim 8, characterized in that: The solvent composition of the hydrobromic acid solution in step (4) is a composition of 1 volume part of 47% hydrobromic acid aqueous solution and 3 volume parts of ethanol.

Images