Nalvidine derivative and high-yield preparation method thereof

Abstract

The method comprises the following steps: S1, dissolving 6-bromoisovanillin and 4-hydroxyphenylethylamine in a first reaction solvent, stirring, adding a reducing agent, carrying out a stirring reaction to obtain an intermediate crude product, and purifying to obtain an intermediate pure product; and S2, adding the pure intermediate product into a second reaction solvent containing an oxidizing agent and alkali, carrying out oxidative cyclization to obtain a crude product of the navidine derivative, and purifying to obtain a navidine derivative product. According to the method disclosed by the invention, 6-bromoisovanillin and tyramine are taken as initial raw materials and are subjected to reduction and oxidative cyclization reaction to obtain the bromo-navidine derivative, and the oxidative cyclization yield can reach 72%; according to the method, the oxidation cost is effectively reduced, the oxidizing agent which is good for the environment is adopted, the use of dangerous and toxic reagents is avoided, the generation of industrial three wastes is effectively reduced, the process is simple, the operation is convenient, the raw materials are cheap and easy to obtain, the yield is high, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a narvidine derivative and a high-yield preparation method thereof. Background Art

[0002] Galantamine was first launched in Austria in 1996 as an acetylcholinesterase (AchE) inhibitor. It was subsequently approved by the European Union for the treatment of varying degrees of Alzheimer's disease (AD). It was subsequently approved by the US FDA in 2001 and by the Japanese PMDA in 2011. In May 2010, Janssen Pharmaceuticals announced that galantamine hydrobromide tablets were officially launched in China for clinical use in the treatment of Alzheimer's disease. Trade name: Reminyl. Galantamine hydrobromide was initially used to reverse neuromuscular blockade, sequelae of poliomyelitis, and myasthenia gravis. It was later developed into a drug for the treatment of mild to moderate AD. Currently, Janssen's galantamine hydrobromide (Reminyl) has been launched in more than 40 countries around the world. As a central cholinesterase inhibitor with good efficacy, mild adverse reactions, and obvious advantages, galantamine has become one of the first choice drugs for the treatment of AD.

[0003] Navidin is an important intermediate for the preparation of galantamine. The synthesis of galantamine uses isovanillin or tyramine and its derivatives as raw materials, and uses phenol coupling to prepare navidin derivatives, and then reduction to obtain the key compound novidin, among which phenol coupling oxidation ring closure is the yield determining reaction.

[0004] In 1968, Kametani's research group improved the method of Barton et al. based on their research. They introduced a bromine group at the 6-position of isovanillin, which increased the oxidative cyclization yield to 40% (Journal Chemistry Society, 1969: 2602-2605).

[0005] In 1995, Carro11 et al. used isovanillin and tyramine as starting materials and obtained brominated navidin derivatives through four steps of condensation, formylation, bromination and oxidation cyclization with potassium ferrocyanide. The oxidation cyclization yield was 43% (Heterocyclicchem., 1995, 32, 195).

[0006] Patent CN101781305A discloses a method for artificially synthesizing galanthamine, in which a dapoxetine derivative is synthesized, but its oxidation cyclization yield is low, about 34%, and the synthesis method uses highly toxic reagents such as toluene and potassium ferrocyanide, which is not environmentally friendly enough, and diatomaceous earth is used in the post-reaction treatment, which increases solid waste.

[0007] The above process has the problems of low yield and high cost, so it is necessary to improve the existing technology to provide a more reliable solution. Summary of the invention

[0008] The technical problem to be solved by the present invention is to provide a narvidine derivative and a high-yield preparation method thereof in view of the deficiencies in the above-mentioned prior art.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is: In the first aspect of the present invention, a high-yield preparation method of a narvidine derivative is provided, comprising the following steps:

[0010] S1, dissolving 6-bromoisovanillin and 4-hydroxyphenylethylamine in a first reaction solvent, stirring, adding a reducing agent, stirring for reaction to obtain a crude intermediate, and purifying to obtain a pure intermediate;

[0011] S2. Add the pure intermediate obtained in step 1 into a second reaction solvent containing an oxidant and a base, obtain a crude narvidine derivative through oxidative cyclization, and purify to obtain a narvidine derivative product.

[0012] The reaction route is as follows:

[0013]

[0014] Preferably, the first reaction solvent is selected from at least one of ethanol, methanol and isopropanol, and most preferably ethanol.

[0015] Preferably, in step S1, the volume of the first reaction solvent is 3 to 20 times the weight of 6-bromoisovanillin, with the unit of volume being mL and the unit of weight being g. For example, it can be 3, 5, 10, 15, 20 times or any value therebetween, and most preferably 5 times.

[0016] Preferably, the reducing agent is selected from at least one of sodium borohydride, potassium borohydride and potassium borohydride, and most preferably is sodium borohydride.

[0017] Preferably, in step S1, the molar ratio of 6-bromoisovanillin to the reducing agent is 1:0.25-1, for example, 1:0.25, 1:0.50, 1:0.75, 1:1 or any value between any two of them, and most preferably 1:0.5.

[0018] Preferably, the molar ratio of 6-bromoisovanillin to 4-hydroxyphenylethylamine is 1:1.0-1.2, for example, 1:1.0, 1:1.05, 1:1.1, 1:1.15, 1:1.2 or any value therebetween, most preferably 1:1.05.

[0019] Preferably, step S1 specifically comprises:

[0020] Dissolve 6-bromoisovanillin and 4-hydroxyphenylethylamine in the first reaction solvent, heat to 40-60°C, keep stirring for 1-4 hours, cool naturally to room temperature, add a reducing agent, stir and react at room temperature for 1-12 hours, adjust the pH of the reaction solution to 5-9 with acid after the reaction, and concentrate under reduced pressure at 40-45°C to obtain a crude intermediate;

[0021] The pH value may be 5 to 6, 6 to 7, 7 to 8, 8 to 9 or any value between them, and the most preferred value is 7 to 8;

[0022] Purification by beating: Add the crude intermediate to the first beating solvent, heat to 65-85°C, stir for 1-4 hours, then cool to room temperature naturally, filter, and air dry the filter cake at 50-70°C for 2-8 hours to obtain a pure intermediate.

[0023] Preferably, in step S1, the first pulping solvent is selected from at least one of methanol, ethanol and isopropanol, and ethanol is most preferred.

[0024] Preferably, the volume of the first pulping solvent is 3 to 10 times the weight of the crude intermediate product, measured in mL by volume and g by weight, for example, 3, 5, 7, 10 times or any value therebetween, and most preferably 5 times.

[0025] Preferably, the acid in step S1 is selected from at least one of hydrochloric acid, formic acid, acetic acid and trifluoroacetic acid, and hydrochloric acid is most preferred.

[0026] Preferably, the oxidant in step S2 is selected from at least one of potassium permanganate, manganese dioxide and hydrogen peroxide, and most preferably hydrogen peroxide.

[0027] Preferably, the amount of the oxidant used is 2.0 to 4.0 eq, for example, 2.0 eq, 2.5 eq, 3.0 eq, 4.0 eq, and most preferably 2.5 eq.

[0028] Preferably, the base in step S2 is selected from at least one of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, and most preferably is sodium carbonate.

[0029] Preferably, the amount of the base used is 2.0 to 4.0 eq, for example, 2.0 eq, 2.5 eq, 3.0 eq, or 4.0 eq, and most preferably 2.5 eq.

[0030] Preferably, the purification process in step S2 is selected from any one of beating, recrystallization, and column chromatography, and beating is most preferred.

[0031] Preferably, the second reaction solvent is composed of an organic solvent and deionized water in a volume ratio of 6:1.0 to 2.0, for example, 6:1.0, 6:1.5, 6:2.0, or any value therebetween, and most preferably 6:1.5.

[0032] Preferably, the volume of the second reaction solvent is 10 to 30 times the weight of the intermediate pure product, with the unit of volume being mL and the unit of weight being g, for example, it can be 10, 20, 25, 30 times or any value therebetween, and most preferably 20 times.

[0033] Preferably, the organic solvent is selected from at least one of chloroform, tetrahydrofuran, ethyl acetate and dioxane, and most preferably ethyl acetate.

[0034] Preferably, step S2 specifically comprises:

[0035] Add the base and the oxidant to the second reaction solvent, stir at room temperature until completely dissolved, then add the intermediate obtained in step 1, stir and react at 40-60° C. for 1.5-6 hours, add an organic solvent to the product after the reaction, stir at room temperature for 15-60 minutes, stand and separate, extract the aqueous phase with an organic solvent, combine the organic phases, and concentrate under reduced pressure at 30-50° C. to obtain a crude navidine derivative;

[0036] Purification: Add the crude navidine derivative into the second slurry solvent, stir for 0.5 to 2 hours, filter with suction, and dry the filter cake at 50 to 70° C. for 2 to 8 hours to obtain the navidine derivative product.

[0037] Preferably, the second pulping solvent is selected from at least one of petroleum ether, dichloromethane and ethyl acetate, and most preferably is ethyl acetate.

[0038] Preferably, the volume of the second slurry solvent is 3 to 10 times the weight of the crude navidine derivative, measured in mL by volume and g by weight, for example, 3, 5, 7, 10 times or any value therebetween, and most preferably 5 times.

[0039] Preferably, in step S2, the beating temperature is 20-80°C, for example, 20°C, 40°C, 60°C, 80°C, and most preferably 40°C.

[0040] The second aspect of the present invention provides a navidin derivative, which is prepared by the method as described above, and the chemical structure of the navidin derivative is as described in the following formula I:

[0041]

[0042] The beneficial effects of the present invention are:

[0043] The present invention provides a navidine derivative and a high-yield preparation method thereof. The method of the present invention uses 6-bromoisovanillin and tyramine as starting materials, and obtains a bromonavidine derivative through reduction and oxidation cyclization reaction. The oxidation cyclization yield can reach 72%. The bromonavidine derivative has the potential to prepare navidine, galanthamine and derivatives thereof.

[0044] The method of the present invention effectively reduces the oxidation cost, adopts an oxidant that is good for the environment, avoids the use of dangerous and toxic reagents, does not require the use of diatomaceous earth in post-reaction treatment, reduces solid waste, effectively reduces the generation of three industrial wastes, and has a simple process, convenient operation, cheap and easily available raw materials, high yield, and is conducive to large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The HPLC spectrum of the navidine derivative product prepared in Example 2;

[0046] Figure 2 This is the LC-MS spectrum of the navidine derivative product prepared in Example 2;

[0047] Figure 3 This is the NMR spectrum of the navidine derivative product prepared in Example 2. DETAILED DESCRIPTION

[0048] 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.

[0049] It should be understood that the 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.

[0050] 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.

[0051] Example 1

[0052] Step 1, Synthesis of Intermediate A

[0053] Add ethanol (2.5L), 6-bromoisovanillin (500.00g) and 4-hydroxyphenylethylamine (311.70g) to a 5L single-mouth bottle, heat to 50°C, stir for 2h, cool to room temperature naturally, add sodium borohydride (40.90g), stir at room temperature for 2h. HPLC monitoring until the remaining 6-bromoisovanillin is less than 0.1%, adjust the pH of the reaction solution to 7-8 with hydrochloric acid (2.0M), and concentrate under reduced pressure at 40-45°C to obtain a crude intermediate: 771.51g of gray solid.

[0054] Step 2: Purification of intermediate pure product

[0055] The crude intermediate was transferred to a 5L three-necked flask, ethanol was added, the temperature was raised to 75°C, stirred for 2 hours, and then naturally cooled to room temperature 25°C. Filtered by suction, the filter cake was dried at 60°C for 4 hours to obtain the pure intermediate: 724.20 g of off-white solid, yield 95.0%.

[0056] Example 2

[0057] Step 1. Synthesis of Navidine Derivatives

[0058] Ethyl acetate (8.0 L), purified water (2.0 L, 4 V), sodium carbonate (376.14 g), and hydrogen peroxide (120.70 g) were added to a 20 L three-necked flask in sequence, and the mixture was stirred at room temperature until the sodium carbonate was completely dissolved. Intermediate A (500.00 g) was then added and stirred at 50 ° C for 3 h. HPLC was monitored until the residual intermediate A was <0.1%. Ethyl acetate (2.5 L) was added to the reaction solution, and the mixture was stirred at room temperature for 0.5 h. The mixture was allowed to stand for separation, and the aqueous phase was extracted twice with ethyl acetate (2.5 L * 2). The organic phases were combined and concentrated under reduced pressure at 40 ° C to obtain a crude product of the navidine derivative: 402.68 g of an off-white solid with a yield of 81.0%.

[0059] Step 2: Purification of navidine derivatives

[0060] The crude product of navidine derivative (402.68 g) was transferred to a 2L three-necked flask, ethyl acetate (2.0 L, 5V) was added, stirred at room temperature for 1 h, filtered, and the filter cake was dried under air at 60°C for 4 h to obtain 357.93 g of navidine derivative product as an off-white solid with a yield of 72.0%.

[0061] Ceravidin derivative product testing:

[0062] HPLC spectrum of navidin derivative products Figure 1 As shown, the HPLC data are as follows: retention time = 2.810 min, product purity > 98.9, absorption wavelength = 287 nm.

[0063] The LC-MS spectra of the cervidine derivatives are as follows Figure 2 As shown, its [M+H] + =350 / 352, matching the molecular weight of the product.

[0064] The NMR spectra of navidin derivatives are as follows Figure 3 As shown, the data is as follows:

[0065] 1H NMR(400MHz,D2O)δ7.21(s,1H),7.10(dd,J=10.4,2.1Hz,1H),6.13(d,J=10.4Hz,1H),5.08–4.83(m,2H),4.4 2(d,J=15.7Hz,1H),3.78(s,3H),3.76-3.73(m,1H).3.62–3.56(m,1H),3.14-3.01(m,2H),2.70–1.98(m,2H).

[0066] 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 high-yield preparation method of a narvidine derivative, characterized in that: The following steps are involved: S1, dissolving 6-bromoisovanillin and 4-hydroxyphenylethylamine in a first reaction solvent, stirring, adding a reducing agent, stirring for reaction to obtain a crude intermediate, and purifying to obtain a pure intermediate; S2. Add the pure intermediate obtained in step 1 into a second reaction solvent containing an oxidant and a base, obtain a crude narvidine derivative through oxidative cyclization, and purify to obtain a narvidine derivative product.

2. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The first reaction solvent is selected from at least one of ethanol, methanol, and isopropanol; The unit of volume is mL and the unit of weight is g. In step S1, the volume of the first reaction solvent is 3 to 20 times the weight of 6-bromoisovanillin.

3. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The reducing agent is selected from at least one of sodium borohydride, potassium borohydride and potassium borohydride.

4. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: In step S1, the molar ratio of 6-bromoisovanillin to the reducing agent is 1:0.25-1, and the molar ratio of 6-bromoisovanillin to 4-hydroxyphenylethylamine is 1:1.0-1.

2.

5. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: Step S1 is specifically as follows: Dissolve 6-bromoisovanillin and 4-hydroxyphenylethylamine in the first reaction solvent, heat to 40-60°C, keep stirring for 1-4 hours, cool naturally to room temperature, add a reducing agent, stir and react at room temperature for 1-12 hours, adjust the pH of the reaction solution to 5-9 with acid after the reaction, and concentrate under reduced pressure at 40-45°C to obtain a crude intermediate; Purification by beating: Add the crude intermediate to the first beating solvent, heat to 65-85°C, stir for 1-4 hours, then cool to room temperature naturally, filter, and air dry the filter cake at 50-70°C for 2-8 hours to obtain a pure intermediate.

6. The high-yield preparation method of narvidine derivatives according to claim 5, characterized in that: In step S1, the first pulping solvent is selected from at least one of methanol, ethanol, and isopropanol; The volume of the first beating solvent is 3 to 10 times the weight of the crude intermediate product, with the unit of volume being mL and the unit of weight being g.

7. The high-yield preparation method of narvidine derivatives according to claim 5, characterized in that: The acid in step S1 is selected from at least one of hydrochloric acid, formic acid, acetic acid and trifluoroacetic acid.

8. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The oxidant in step S2 is selected from at least one of potassium permanganate, manganese dioxide and hydrogen peroxide, and the amount of the oxidant is 2.0 to 4.0 eq.

9. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The base in step S2 is selected from at least one of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, and the amount of the base used is 2.0 to 4.0 eq.

10. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The purification process in step S2 is selected from any one of beating, recrystallization and column chromatography.

11. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: The second reaction solvent is composed of an organic solvent and deionized water in a volume ratio of 6:1.0-2.

0. The volume unit is mL and the weight unit is g. The volume of the second reaction solvent is 10-30 times the weight of the intermediate pure product.

12. The high-yield preparation method of narvidine derivatives according to claim 11, characterized in that: The organic solvent is selected from at least one of chloroform, tetrahydrofuran, ethyl acetate and dioxane.

13. The high-yield preparation method of narvidine derivatives according to claim 1, characterized in that: Step S2 is specifically as follows: Add the base and the oxidant to the second reaction solvent, stir at room temperature until completely dissolved, then add the intermediate obtained in step 1, stir and react at 40-60° C. for 1.5-6 hours, add an organic solvent to the product after the reaction, stir at room temperature for 15-60 minutes, stand and separate, extract the aqueous phase with an organic solvent, combine the organic phases, and concentrate under reduced pressure at 30-50° C. to obtain a crude navidine derivative; Purification: Add the crude navidine derivative into the second slurry solvent, stir for 0.5 to 2 hours, filter with suction, and dry the filter cake at 50 to 70° C. for 2 to 8 hours to obtain the navidine derivative product.

14. The high-yield preparation method of narvidine derivatives according to claim 13, characterized in that: The second beating solvent is selected from at least one of petroleum ether, dichloromethane and ethyl acetate. The volume of the second beating solvent is 3 to 10 times the weight of the crude navidine derivative, measured in mL by volume and g by weight.

15. The high-yield preparation method of narvidine derivatives according to claim 14, characterized in that: In step S2, the beating temperature is 20-80°C.

16. A navidine derivative, characterized in that: It is prepared by the method according to any one of claims 1 to 15, and the chemical structure of the navidine derivative is as shown in the following formula I:

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