A galanthamine intermediate derivative and a catalytic oxidation preparation method thereof

Abstract

The invention discloses a galanthamine intermediate derivative and a catalytic oxidation preparation method thereof, the method comprising the following steps: N-formyl-1-bromo-navidin is subjected to an oxidation reaction by blowing air under the catalytic action of a catalyst in an aprotic solvent, followed by an acidification treatment to obtain the galanthamine intermediate derivative. The invention avoids the hydrolysis reaction of amides under strong acid or strong base conditions, can reduce various potential side reactions, improves the reaction yield, and has a simple process, is green and environmentally friendly, is conducive to subsequent separation and purification, and can achieve industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a galanthamine intermediate derivative and a catalytic oxidation 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] In the preparation process of the galanthamine intermediate derivatives involved in the present invention, according to the usual synthesis method, a hydrolysis reaction of the amide under strong acid or strong base conditions is generally selected to obtain the target product. However, whether it is a strong acid or a strong base, the conditions are too strong, and there are often some unexpected side reactions. For example, under strong acid conditions, the furan ring and the phenol methyl ether will be partially destroyed, and under strong alkaline conditions, the target product will have many side reactions with the raw materials such as Michael addition or Aldol condensation, which seriously affects the synthesis yield and brings huge challenges to the subsequent separation operation. Therefore, it is necessary to propose a new mild and efficient preparation method of galanthamine derivatives to solve some problems existing in the above process. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a galanthamine intermediate derivative and a catalytic oxidation preparation method thereof in view of the deficiencies in the above-mentioned prior art. The present invention uses commercially available galanthamine intermediate N-formyl-1-bromo-navidine as a raw material, and uses ferric chloride to catalyze air oxidation under mild conditions to obtain a galanthamine intermediate derivative.

[0005] To achieve the above object, the technical solution adopted by the present invention is: In the first aspect of the present invention, a galanthamine intermediate derivative is provided, which has a chemical structure shown in the following formula II:

[0006] .

[0007] The second aspect of the present invention provides a method for preparing the galanthamine intermediate derivative by catalytic oxidation as described above, and the reaction scheme is as follows:

[0008] .

[0009] The specific steps include:

[0010] N-formyl-1-bromo-navidine is oxidized by blowing air in an aprotic solvent under the catalytic action of a catalyst, and then subjected to an acidification treatment to obtain a galanthamine intermediate derivative;

[0011] The chemical structure of N-formyl-1-bromo-navidin is shown in the following formula I:

[0012] .

[0013] Reaction process: The hydrogen atom of the formyl group undergoes SET single electron transfer under the action of ferric chloride to generate an acyl radical. At this time, the trivalent iron ion obtains an electron to become a divalent ferrous ion. The acyl radical then reacts with oxygen in the air to obtain a peroxide radical. The peroxide radical then takes an electron from the divalent ferrous ion to generate a peroxy acid anion. At this time, the ferrous ion is oxidized to a trivalent iron ion catalyst to complete the cycle. The peroxy acid anion acts as a nucleophile to attack the carbonyl group of the formyl group to obtain a nucleophilic addition product of the two, and then intramolecular electron migration occurs. Finally, two molecules of carbon dioxide are removed under the action of hydrochloric acid to obtain the target product.

[0014] The reaction mechanism is as follows:

[0015] .

[0016] Preferably, the catalyst is ferric chloride.

[0017] Preferably, the reaction time of the oxidation reaction is 3 to 6 hours, for example, 3, 4, 5, 6 hours or any value therebetween, and most preferably 5 hours.

[0018] Preferably, the reaction temperature of the oxidation reaction is 10-30°C, for example, 10°C, 20°C, 25°C, 30°C or any value therebetween, and most preferably 25°C.

[0019] Preferably, the molar ratio of the catalyst to N-formyl-1-bromo-navidine is 0.25:1 to 0.10:1, for example, 0.25:1, 0.15:1, 0.10:1 or any value between them, and most preferably 0.10:1.

[0020] Preferably, the aprotic solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, and dimethyl sulfoxide is most preferred.

[0021] Preferably, the volume of the aprotic solvent is 5 to 10 times the mass of N-formyl-1-bromo-navidin, with the unit of volume being mL and the unit of weight being g, for example, it can be 5, 7, 9, 10 times or any value between them, and most preferably 8 times.

[0022] Preferably, the catalytic oxidation preparation method of the galanthamine intermediate derivative comprises the following steps:

[0023] Add N-formyl-1-bromo-navidin to a non-protonic solvent, stir to dissolve, add a catalyst, and react with air at 10-30°C for 3-6 hours;

[0024] After the reaction is completed, the reaction solution is poured into ice water, the pH is adjusted with hydrochloric acid, and then extracted with dichloromethane several times. After the dichloromethane phases are combined, they are washed with pure water and saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the obtained crude product is purified by reverse HPLC to obtain a galanthamine intermediate derivative.

[0025] Preferably, the pH is adjusted to 3 to 4 using hydrochloric acid having a concentration of 0.5-2 mol / L. The concentration of the hydrochloric acid is more preferably 1 mol / L.

[0026] The beneficial effects of the present invention are:

[0027] The present invention provides a mild and efficient preparation method of galanthamine derivatives based on catalytic oxidation and the galanthamine derivatives. The present invention avoids the hydrolysis reaction of amides under strong acid or strong base conditions, can reduce various potential side reactions, improves the reaction yield, and has a simple process, is green and environmentally friendly, is conducive to subsequent separation and purification, and can realize industrial large-scale production. The galanthamine derivatives provided by the present invention have the potential to be used in the synthesis of galanthamine, dihydrogalanthamine and related impurities of galanthamine, and have good market application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the NMR spectrum of the galanthamine intermediate derivative prepared in Example 1. DETAILED DESCRIPTION

[0029] 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.

[0030] 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.

[0031] 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. Example 1

[0032] A method for preparing a galanthamine intermediate derivative by catalytic oxidation, the synthetic route of which is as follows:

[0033]

[0034] The specific steps are as follows:

[0035] Add 30 ml of dimethyl sulfoxide to a 50 ml three-necked flask, then add N-formyl-1-bromo-navidine (3.78 g, 0.01 mol), stir to dissolve, add anhydrous ferric chloride (0.16 g, 0.001 mol) at once, and react at room temperature at 25 ° C with air for 5 hours. After TLC monitoring, the reaction solution is poured into cold water, and then the pH is adjusted to 3 with 1 mol / L hydrochloric acid, extracted with dichloromethane three times, the dichloromethane phase is combined and washed with water once, washed with saturated sodium chloride aqueous solution once, dried over anhydrous sodium sulfate, filtered and concentrated; the crude product obtained by concentration is purified by reverse HPLC (reverse phase high performance liquid chromatography), and finally 3.56 g of white solid: galanthamine intermediate derivative is obtained, with a yield of 92.01%.

[0036] The NMR spectrum of the galanthamine intermediate derivative prepared in this example is as follows Figure 1 As shown, the NMR data are as follows:

[0037] 1H NMR (400 MHz, D2O) δ 7.30 (s, 1H), 7.19 (dd, J =10.0, 2.0Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 5.09 – 5.02 (m, 2H), 4.50 (d, J = 16.0 Hz, 1H),3.87 (s, 3H), 3.84-3.72(m, 1H), 3.72-3.65(m, 1H), 3.22 – 3.11 (m, 2H), 2.53-2.49(m, 1H), 2.34-2.42 (m, 1H). Example 2

[0038] A method for preparing a galanthamine intermediate derivative by catalytic oxidation, the synthetic route of which is as follows:

[0039]

[0040] The specific steps are as follows:

[0041] Add 20ml N,N-dimethylformamide to a 50ml three-necked flask, then add N-formyl-1-bromo-navidine (3.78g, 0.01mol), stir to dissolve, add anhydrous ferric chloride (0.32g, 0.002mol) at once, and react at room temperature at 25℃ with air for 3h. After the TLC reaction is complete, pour the reaction solution into cold water, adjust the pH to 3-4 with 1mol / L hydrochloric acid, extract with dichloromethane three times, wash the dichloromethane phase with water once, wash with saturated sodium chloride solution once, dry with anhydrous sodium sulfate, filter and concentrate; the crude product obtained by concentration is purified by reverse HPLC to finally obtain 3.26g of white solid: galanthamine intermediate derivative, with a yield of 84.39%.

[0042] 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 a galanthamine intermediate derivative by catalytic oxidation, characterized in that: The galanthamine intermediate derivative has a chemical structure as shown in the following formula II: ； The catalytic oxidation preparation method of the galanthamine intermediate derivative comprises the following steps: N-formyl-1-bromo-navidine is oxidized by blowing air in an aprotic solvent under the catalytic action of a catalyst, and then subjected to an acidification treatment to obtain a galanthamine intermediate derivative; The chemical structure of N-formyl-1-bromo-navidin is shown in the following formula I: ； The catalyst is ferric chloride; The reaction temperature of the oxidation reaction is 10~30℃; The molar ratio of the catalyst to N-formyl-1-bromo-navidine is 0.25:1 to 0.10:1; The aprotic solvent is selected from dimethyl sulfoxide and N,N-dimethylformamide.

2. The method for preparing a galanthamine intermediate derivative by catalytic oxidation according to claim 1, characterized in that: The reaction time of the oxidation reaction is 3~6h.

3. The method for preparing a galanthamine intermediate derivative by catalytic oxidation according to claim 1, characterized in that: The volume of the aprotic solvent is 5 to 10 times the mass of N-formyl-1-bromo-navidin, with the unit of volume being mL and the unit of weight being g.

4. The method for preparing a galanthamine intermediate derivative by catalytic oxidation according to claim 1, characterized in that: The following steps are involved: Add N-formyl-1-bromo-navidin to a non-protonic solvent, stir to dissolve, add a catalyst, and react with air at 10-30°C for 3-6 hours; After the reaction is completed, the reaction solution is poured into ice water, the pH is adjusted with hydrochloric acid, and then extracted with dichloromethane several times. After the dichloromethane phases are combined, they are washed with pure water and saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the obtained crude product is purified by reverse HPLC to obtain a galanthamine intermediate derivative.

5. The method for preparing a galanthamine intermediate derivative by catalytic oxidation according to claim 4, characterized in that: in, Use 0.5-2mol / L hydrochloric acid to adjust the pH to 3-4.

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