Benzoyl galanthamine and preparation method thereof

Abstract

The invention discloses benzoyl galanthamine hydrochloride and a preparation method thereof.The preparation method comprises the steps that sodium carbonate, benzoyl chloride and the like which are low in price and easy to obtain serve as raw materials and react in DCM at the normal temperature to obtain a benzoyl galanthamine crude product, then the benzoyl galanthamine crude product is converted into hydrochloride, recrystallization and purification are conducted, and the target product benzoyl galanthamine hydrochloride is obtained; the method has the advantages of mild process reaction conditions and high yield, effectively reduces the synthesis cost, avoids the use of dangerous and toxic reagents, and effectively reduces the generation of industrial three wastes; the process is simple, operation is convenient, raw materials are cheap and easy to obtain, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to benzoylgalanthamine and a preparation method thereof. Background Art

[0002] Galanthamine is a drug extracted from plants. Its chemical name is Galanthamine. It belongs to the second generation of competitive cholinesterase inhibitors. It is highly specific for neuronal acetylcholinesterase and is mainly used to treat Alzheimer's disease (AD). Alzheimer's disease (AD) is a primary degenerative disease of the central nervous system. It is more common in pre-senile and senile dementia. The onset is insidious and the course of the disease is progressive. AD patients account for 55% of dementia patients. The prevalence rate is 5% to 8%, and the prevalence rate increases with age. Cholinergic deficiency plays an important role in the pathogenesis of Alzheimer's disease. The cholinergic system is also necessary to maintain a person's short-term memory and attention. The cholinergic system dysfunction is also related to the occurrence of certain neuropsychiatric symptoms and behaviors in patients. Cholinesterase inhibitors play an important role in the current treatment of Alzheimer's disease (AD). Galanthamine is a second generation AchE inhibitor with a dual mechanism of action. It can better stimulate and inhibit AchE, increase the level of acetylcholine in the brain, and delay the process of brain cell dysfunction. It can significantly improve the cognitive function of mild and moderate AD patients and maintain their daily living ability. Therefore, the study of galantamine or galantamine derivatives has important scientific significance and will surely make a huge contribution and help to mankind to overcome Alzheimer's disease (AD) as soon as possible.

[0003] Traditional methods for synthesizing galanthamine derivatives generally use relatively expensive condensation agents such as EDC, and have problems such as harsh reaction conditions and / or low yield. Therefore, it is necessary to propose a new mild and efficient method for preparing galanthamine derivatives to solve the above problems. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a benzoylgalanthamine and a preparation method thereof in view of the deficiencies in the above-mentioned prior art.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing benzoylgalanthamine, the reaction scheme is as follows:

[0006]

[0007] The specific steps include:

[0008] S1. Preparation of free galantamine:

[0009] Dissolve galanthamine hydrobromide in water, adjust the pH to 7-8 with alkali, then extract the system several times with DCM (dichloromethane), and spin dry to obtain free galanthamine;

[0010] S2, preparation of crude benzoylgalanthamine:

[0011] The free galanthamine prepared in step S1 is dried, dissolved in DCM, and then sodium carbonate is added, and benzoyl chloride is added dropwise at a first temperature under nitrogen protection. After the addition is complete, the mixture is reacted at a second temperature to obtain a crude benzoylgalanthamine product;

[0012] S3, purification of crude benzoylgalanthamine:

[0013] The crude benzoylgalanthamine prepared in step S2 is washed with hydrochloric acid, a saturated sodium bicarbonate solution and pure water in sequence, the organic phase is dried with anhydrous sodium sulfate, and concentrated to obtain pure benzoylgalanthamine;

[0014] S4, preparation of crude benzoylgalanthamine hydrochloride:

[0015] The pure benzoylgalanthamine prepared in step S3 is dried and dissolved in ethanol, and hydrochloric acid is added dropwise at the third temperature until a white solid is precipitated, and after the addition is completed, the mixture is stirred and filtered to obtain a crude benzoylgalanthamine hydrochloride;

[0016] S5. Purification of crude benzoylgalanthamine hydrochloride:

[0017] The crude benzoylgalanthamine hydrochloride prepared in step S4 is dried, added to a water-ethanol solution for recrystallization, filtered, rinsed with ethanol, and dried to obtain a pure benzoylgalanthamine hydrochloride with a purity of more than 98%;

[0018] S6. Free benzoylgalantamine hydrochloride:

[0019] The pure benzoylgalanthamine hydrochloride obtained in step S5 is dissolved in 10V (based on the dry mass of benzoylgalanthamine hydrochloride) of pure water, the pH is adjusted to 7-8 with sodium bicarbonate at 0°C, extracted 3-5 times with DCM 10V (based on the dry mass of benzoylgalanthamine hydrochloride), dried over anhydrous sodium sulfate and concentrated to obtain benzoylgalanthamine as a white solid.

[0020] Preferably, the base in step S1 is selected from at least one of sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and most preferably is sodium bicarbonate.

[0021] Preferably, the first temperature in step S2 is -10 to 10°C, most preferably 0°C.

[0022] Preferably, the second temperature in step S2 is 0-40°C, and can be any temperature in this range, but is most preferably 25°C.

[0023] Preferably, in step S2, the reaction time at the second temperature is 6 to 20 hours, which can be any time in this range, but is most preferably 8 hours.

[0024] Preferably, the volume of DCM in step S2 is 5 to 20 times the dry weight of free galanthamine, with the unit of volume being L and the unit of weight being kg. It can be any multiple thereof, but most preferably is 10 times.

[0025] Preferably, in step S3, the washing temperature is 25°C and the concentration of the hydrochloric acid used is 1M;

[0026] In terms of volume in L and weight in kg, in step S3, the volume of hydrochloric acid is 5 to 30 times the mass of the free galanthamine dry mass, which may be any multiple thereof, but most preferably is 10 times; the volume of the saturated sodium bicarbonate solution is 5 to 30 times the mass of the free galanthamine dry mass, which may be any multiple thereof, but most preferably is 10 times; the volume of pure water is 5 to 30 times the mass of the free galanthamine dry mass, which may be any multiple thereof, but most preferably is 10 times.

[0027] Preferably, with the unit of volume being L and the unit of weight being kg, in step S4, the volume of ethanol is 2 to 20 times the dry mass of the crude benzoylgalanthamine, which may be any multiple thereof, but most preferably is 10 times.

[0028] Preferably, the third temperature in step S4 is -10 to 10°C, and may be any temperature in this range, but is most preferably 0°C.

[0029] Preferably, the mass percentage of water in the hydroethanol solution in step S5 is 1-15%, and the water content can be a certain value in between, but 10% is the optimal water content.

[0030] Preferably, the volume of the aqueous ethanol solution is 3 to 10 times the dry mass of the crude benzoylgalanthamine hydrochloride product, with the unit of volume being L and the unit of weight being kg. It can be any multiple thereof, but most preferably is 10 times.

[0031] Preferably, the volume of ethanol used for elution in step S5 is 0.5 to 10 times the dry mass of the crude benzoylgalanthamine hydrochloride product, expressed in units of volume as L and weight as kg, and may be any multiple thereof, but most preferably is 2 times.

[0032] The present invention also provides benzoylgalanthamine, which is prepared by the method as described above; its structural formula is shown in the following formula 1:

[0033]

[0034] The beneficial effects of the present invention are:

[0035] The invention provides a benzoylgalanthamine and a preparation method thereof. The invention uses cheap and readily available sodium carbonate, benzoyl chloride and the like as raw materials, reacts in DCM at room temperature to obtain a crude benzoylgalanthamine product, then converts the crude benzoylgalanthamine into a hydrochloride, and then recrystallizes and purifies the crude benzoylgalanthamine product to obtain a target product, benzoylgalanthamine hydrochloride.

[0036] The process of the invention has mild reaction conditions and high yield, effectively reduces the synthesis cost, avoids the use of dangerous and toxic reagents, and effectively reduces the generation of industrial wastes; and the process is simple, the operation is convenient, and the raw materials are cheap and easily available, which is conducive to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The chromatographic analysis results of the pure benzoylgalanthamine prepared in Example 1. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0039] It should be understood that terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0040] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0041] Example 1

[0042] A method for preparing benzoylgalantamine comprises the following steps:

[0043] S1. Preparation of free galantamine:

[0044] 20 L of pure water was added to a 50 L reactor, galanthamine hydrobromide (2 kg) was added to dissolve, and then the pH was adjusted to 7-8 with sodium bicarbonate, the aqueous phase was extracted 6 times with 20 L of DCM, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 1.8 kg of free galanthamine.

[0045] S2, preparation of crude benzoylgalanthamine:

[0046] Add 18 L of DCM to a 50 L reactor, add the dry free galanthamine (1.8 kg, 1.94 mol) obtained in step 1 under constant stirring, then add sodium carbonate (606.29 g, 4.65 mol), protect the system with nitrogen, and add benzoyl chloride (2.4 L, 2.86 mol) dropwise at 0 ° C. After the addition is complete, stir the reaction at 25 ° C for 8 h to obtain crude benzoylgalanthamine.

[0047] S3, purification of crude benzoylgalanthamine:

[0048] At 25°C, the organic phase was washed with 18 L of 1M hydrochloric acid, then with 18 L of saturated sodium bicarbonate, and finally with 18 L of water. After drying with anhydrous sodium sulfate, the organic phase was concentrated and dried to obtain 2.05 kg of pure benzoylgalanthamine.

[0049] S4, preparation of crude benzoylgalanthamine hydrochloride:

[0050] 2.05 kg of pure benzoylgalanthamine was dissolved in 20.5 L of ethanol, and 1.3 M HCl was added dropwise at 0°C until a white solid precipitated, then the addition was stopped, and the mixture was stirred at room temperature for 2 h. The mixture was filtered and then dried to obtain 1.94 kg of crude benzoylgalanthamine hydrochloride (white solid product), with a yield of 95.47%.

[0051] S5. Purification of crude benzoylgalanthamine hydrochloride:

[0052] 1.94 kg of crude benzoylgalanthamine hydrochloride was added to 19.4 L of 10% (volume concentration) water-ethanol solution, heated to 78° C. to dissolve, cooled naturally to room temperature, stirred and crystallized, and a large amount of white solid precipitated after 2 hours. The solid was filtered and rinsed with 3.88 L of ethanol to obtain 1.85 kg of pure benzoylgalanthamine hydrochloride with a yield of 97.65%.

[0053] S6, free benzoylgalantamine hydrochloride

[0054] 1.85 kg of the obtained benzoylgalanthamine hydrochloride was dissolved in 18.5 L of water, and the pH was adjusted to 7-8 with sodium bicarbonate at 0°C, extracted three times with 18.5 L of DCM, dried over anhydrous sodium sulfate, and concentrated to obtain 1.65 kg of pure benzoylgalanthamine in the form of a white powdery solid with a yield of 98.3%.

[0055] Reference Figure 1 , is the chromatographic analysis result of the pure benzoylgalanthamine prepared in this example.

[0056] Example 2

[0057] S1. Preparation of free galantamine:

[0058] Add 2L of pure water to a 5L reactor, add galanthamine hydrobromide (0.2kg) to dissolve, then adjust the pH to 7-8 with sodium bicarbonate, extract the aqueous phase 6 times with 2L of DCM, dry the organic phase with anhydrous sodium sulfate and concentrate to obtain 0.18kg of free galanthamine.

[0059] S2, preparation of crude benzoylgalanthamine:

[0060] Add 1.8 L of DCM to a 5 L reactor, add the dry free galanthamine (0.18 kg, 0.194 mol) obtained in step 1 under constant stirring, then add sodium carbonate (60.69 g, 0.465 mol), protect the system with nitrogen, and add benzoyl chloride (0.24 L, 0.286 mol) dropwise at 0 ° C. After the addition is complete, stir the reaction at 25 ° C for 8 h to obtain crude benzoylgalanthamine.

[0061] S3, purification of crude benzoylgalanthamine:

[0062] At 25°C, the organic phase was washed with 1.8 L of 1M hydrochloric acid, then with 1.8 L of saturated sodium bicarbonate, and finally with 1.8 L of water. After drying with anhydrous sodium sulfate, the organic phase was concentrated and dried to obtain 0.223 kg of crude pure benzoylgalanthamine.

[0063] S4, preparation of crude benzoylgalanthamine hydrochloride:

[0064] 0.223 kg of pure benzoylgalanthamine was dissolved in 2.2 L of ethanol, and 1.3 M HCl was added dropwise at 0°C until a white solid precipitated. The addition was stopped, and the mixture was stirred at room temperature for 2 h. The mixture was then filtered and dried to obtain 0.19 kg of crude benzoylgalanthamine hydrochloride (white solid product) with a yield of 95.44%.

[0065] S5. Purification of crude benzoylgalanthamine hydrochloride:

[0066] 0.19 kg of crude benzoylgalanthamine hydrochloride was added to 1.9 L of 10% (volume concentration) aqueous ethanol solution, heated to 78° C. to dissolve, cooled naturally to room temperature, stirred and crystallized. After 2 h, a large amount of white solid precipitated, which was filtered and rinsed with 0.38 L of ethanol to obtain 0.19 kg of pure benzoylgalanthamine hydrochloride with a yield of 97.75%.

[0067] S6, free benzoylgalantamine hydrochloride

[0068] 0.19 kg of the obtained benzoylgalanthamine hydrochloride was dissolved in 1.9 L of water, the pH was adjusted to 7-8 with sodium bicarbonate at 0°C, extracted three times with 1.9 L of DCM, dried over anhydrous sodium sulfate, and concentrated to obtain 0.17 kg of pure benzoylgalanthamine as a white powdery solid with a yield of 97.7%.

[0069] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing benzoylgalantamine, characterized in that, The following steps are involved: S1. Preparation of free galantamine: Dissolve galanthamine hydrobromide in water, adjust the pH to 7-8 with alkali, then extract the system with DCM several times, and spin dry to obtain free galanthamine; S2, preparation of crude benzoylgalanthamine: The free galanthamine prepared in step S1 is dried, dissolved in DCM, and then sodium carbonate is added, and benzoyl chloride is added dropwise at a first temperature under nitrogen protection. After the addition is complete, the mixture is reacted at a second temperature to obtain a crude benzoylgalanthamine product; S3, purification of crude benzoylgalanthamine: The crude benzoylgalanthamine prepared in step S2 is washed with hydrochloric acid, a saturated sodium bicarbonate solution and pure water in sequence, the organic phase is dried with anhydrous sodium sulfate, and concentrated to obtain pure benzoylgalanthamine; S4, preparation of crude benzoylgalanthamine hydrochloride: The pure benzoylgalanthamine prepared in step S3 is dried and dissolved in ethanol, and hydrochloric acid is added dropwise at the third temperature until a white solid is precipitated, and after the addition is completed, the mixture is stirred and filtered to obtain a crude benzoylgalanthamine hydrochloride; S5. Purification of crude benzoylgalanthamine hydrochloride: The crude benzoylgalanthamine hydrochloride prepared in step S4 is dried, added to a water-ethanol solution for recrystallization, filtered, rinsed with ethanol, and dried to obtain a pure benzoylgalanthamine hydrochloride; S6. Free benzoylgalantamine hydrochloride: Pure benzoylgalantamine was obtained by free extraction with sodium bicarbonate.

2. The method for preparing benzoylgalanthamine according to claim 1, wherein The alkali in step S1 is selected from at least one of sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

3. The preparation method of benzoylgalanthamine according to claim 1, characterized in that, The first temperature in step S2 is -10 to 10°C.

4. The method for preparing benzoylgalanthamine according to claim 1, wherein The second temperature in step S2 is 0-40° C., and the reaction time at the second temperature in step S2 is 6-20 hours.

5. The preparation method of benzoylgalanthamine hydrochloride according to claim 1, characterized in that, The volume of DCM in step S2 is 5 to 20 times the dry weight of free galanthamine, with the unit of volume being L and the unit of weight being kg.

6. The method for preparing benzoylgalanthamine hydrochloride according to claim 1, wherein In step S3, the washing temperature is 25°C and the concentration of hydrochloric acid used is 1M; With the unit of volume being L and the unit of weight being kg, in step S3, the volume of hydrochloric acid is 5 to 30 times the mass of the free galanthamine dry mass, the volume of the saturated sodium bicarbonate solution is 5 to 30 times the mass of the free galanthamine dry mass, and the volume of pure water is 5 to 30 times the mass of the free galanthamine dry mass.

7. The method for preparing benzoylgalanthamine hydrochloride according to claim 1, wherein The unit of volume is L and the unit of weight is kg. In step S4, the volume of ethanol is 2 to 20 times the dry weight of the crude benzoylgalanthamine.

8. The method for preparing benzoylgalanthamine hydrochloride according to claim 1, wherein The third temperature in step S4 is -10 to 10°C.

9. The method for preparing benzoylgalanthamine hydrochloride according to claim 1, wherein The volume percentage of water in the hydroethanol solution in step S5 is 1 to 15%; The volume of the aqueous ethanol solution is 3 to 10 times the dry mass of the crude benzoylgalanthamine hydrochloride product, with the unit of volume being L and the unit of weight being kg.

10. The method for preparing benzoylgalanthamine hydrochloride according to claim 1, characterized in that: The volume of ethanol used for elution in step S5 is 0.5 to 10 times the dry weight of the crude benzoylgalanthamine hydrochloride product, with the unit of volume being L and the unit of weight being kg.

11. A benzoylgalantamine, characterized in that: It is prepared by the method according to any one of claims 1 to 10.

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