A method for synthesizing key intermediates of galantamine via photocatalytic microchannels

Abstract

This invention discloses a method for synthesizing a key intermediate of galantamine using a photocatalytic microchannel reactor, comprising the following steps: S1: Using intermediate II as a raw material, porphyrin compounds are used as photocatalysts and oxygen as an oxidant in a photocatalytic microchannel reactor under light irradiation to generate intermediate I. The resulting reaction solution is then post-treated to obtain crude intermediate I, which is then purified by recrystallization to obtain pure intermediate I, i.e., the key intermediate of galantamine. This invention uses intermediate II as a raw material, and under photocatalysis, utilizes a photocatalytic microchannel reactor with oxygen as an oxidant to oxidize intermediate I under light irradiation. The resulting reaction solution is then post-treated to obtain crude intermediate I, which is further purified by recrystallization to obtain pure intermediate I. This method has a series of advantages, including good process stability, excellent reaction selectivity, high yield, and readily available and inexpensive raw materials, simple operation, high safety, and environmental friendliness.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a method for synthesizing a key intermediate of galantamine via photocatalytic microchannels. Background Technology

[0002] With the rapid aging of the population worldwide, neurodegenerative diseases such as Alzheimer's disease are increasingly becoming social problems that society urgently needs to address and solve. Galantamine is a cholinesterase inhibitor, mainly used to treat mild to moderate Alzheimer's disease. It can enhance nerve signal transmission by increasing the level of acetylcholine in the brain, thereby improving cognitive functions such as memory and attention in Alzheimer's patients. In addition, galantamine is also used clinically to treat sequelae of poliomyelitis (poliomyelitis), muscle atrophy, and myasthenia gravis. It can also be used for cerebral palsy in children, post-traumatic sensory and motor disorders, polyneuritis, and spinal radiculitis.

[0003] Intermediate I (CAS: 252869-09-3) is a key intermediate in the synthesis of galantamine. Existing technologies primarily utilize the process reported in patent US6043359A: using intermediate II (CAS: 122584-18-3) as a raw material, potassium ferricyanide as an oxidant, and toluene and water as solvents, oxidative cyclization is performed in the presence of potassium carbonate to generate intermediate I. However, this process involves a large solvent volume, low production efficiency, high requirements for mixing efficiency, and low yield. Furthermore, the waste liquid contains a large amount of highly toxic cyanide anions, posing significant safety hazards. The chemical structures of intermediates I and II are shown below:

[0004] .

[0005] Patent BG103117A discloses a method for preparing navir-type enol and its derivatives. Although the process used has improved the yield, it requires expensive 1,1,1,3,3,3-hexafluoroisopropanol as a solvent and trifluoroacetyliodobenzene as an oxidant, resulting in high raw material costs and making it unsuitable for industrial production.

[0006] Therefore, it is necessary to improve existing technologies to provide more reliable solutions. Summary of the Invention

[0007] The technical problem to be solved by this invention is to address the shortcomings of the prior art by providing a method for synthesizing key intermediates of galantamine using a photocatalytic microchannel approach. This invention provides a scheme using intermediate II as a raw material and employing photocatalytic microchannels for the synthesis of galantamine intermediates. This scheme significantly improves the yield of galantamine intermediate I and has advantages such as readily available and inexpensive raw materials, high production efficiency, stable process, simple operation, high safety, and environmental friendliness.

[0008] To achieve the above objectives, the technical solution adopted by this invention is: a method for synthesizing a key intermediate of galantamine via photocatalytic microchannels, comprising the following steps:

[0009] S1: Using intermediate II as raw material, intermediate I is generated by oxidizing it under light using a photocatalytic microchannel reactor with porphyrin compounds as photocatalysts and oxygen as oxidant. The crude intermediate I is then obtained through post-processing.

[0010] S2: The crude intermediate I was recrystallized and purified to obtain the pure intermediate I, which is the key intermediate of galantamine.

[0011] The preparation route of intermediate I is as follows:

[0012] .

[0013] Preferably, step S1 specifically includes:

[0014] Intermediate II and the photocatalyst were dissolved in a first organic solvent to obtain a reaction solution. The reaction solution was then fed into a photocatalytic microchannel reactor, and oxygen was introduced into the reactor. The reaction was carried out under ultraviolet light irradiation. After the reaction was completed, crude intermediate I was obtained through post-processing.

[0015] Preferably, the photocatalyst is at least one selected from tetraphenylporphyrin, tetra(4-methylphenyl)porphyrin, tetra(4-methoxyphenyl)porphyrin, and (4-chlorophenyl)porphyrin; more preferably, the photocatalyst is tetraphenylporphyrin.

[0016] Preferably, the molar ratio of the photocatalyst to intermediate II is 0.002 to 0.014:1; for example, the ratio is 0.002:1, 0.004:1, 0.006:1, 0.008:1, 0.01:1, 0.012:1, 0.014:1 or any value formed by any two of them; more preferably, the ratio is 0.006:1.

[0017] Preferably, the first organic solvent is at least one of dichloromethane, toluene, chloroform, and 1,2-dichloroethane; more preferably, the solvent is chloroform.

[0018] Preferably, the volume ratio of the first organic solvent to the mass ratio of intermediate II is 10 to 50:1, for example, the ratio is 10:1, 20:1, 30:1, 40:1, 50:1 or any combination thereof; more preferably, the ratio is 30:1 to effectively reduce the occurrence of side reactions.

[0019] Preferably, in step S1, the reaction solution is injected into the photocatalytic microchannel reactor at a flow rate of 20-80 mL / min, for example, the flow rate is 20 mL / min, 30 mL / min, 40 mL / min, 50 mL / min, 70 mL / min, 80 mL / min or any value formed by any combination of these, more preferably, the flow rate is 50 mL / min.

[0020] Preferably, oxygen is introduced into the photocatalytic microchannel reactor at a flow rate of 100-200 mL / min, for example, at a flow rate of 100 mL / min, 120 mL / min, 140 mL / min, 160 mL / min, 180 mL / min, 200 mL / min or any combination thereof; more preferably, the flow rate is 150 mL / min.

[0021] Preferably, the wavelength of the ultraviolet light source applied in step S1 is 300~420nm, more preferably, the wavelength is 365nm.

[0022] Preferably, the power of the ultraviolet light source applied in step S1 is 180~540 W; more preferably, the power is 360 W.

[0023] Preferably, in step S1, the temperature of the photocatalytic microchannel reactor is controlled to be 10~30℃, for example, 10, 20, 30, 40, 50℃ or any value formed by any two of them; more preferably, it is 30℃.

[0024] Preferably, in step S1, the residence time of the reaction solution in the photocatalytic microchannel reactor is controlled to be 3 to 8 min; for example, the residence time is 3, 4, 5, 6, 7, 8 min or any value formed by any two of them, more preferably 5 min.

[0025] Preferably, step S1 specifically includes:

[0026] Intermediate II and the photocatalyst were dissolved in a first organic solvent and stirred until homogeneous to obtain a reaction solution. The reaction solution was pumped into a photocatalytic microchannel reactor at a flow rate of 20-80 mL / min using a plunger pump, and oxygen was introduced into the photocatalytic microchannel reactor at a flow rate of 100-200 mL / min. The temperature of the photocatalytic microchannel reactor was controlled at 10-30℃, and an ultraviolet light source with a power of 180-540 W and a wavelength of 300-420 nm was turned on. The residence time of the reaction solution in the photocatalytic microchannel reactor was controlled at 3-8 min. After the reaction was completed, the reaction product was washed sequentially with 0.5-2N hydrochloric acid solution, 2.5-10 wt% sodium bicarbonate solution, and 5-20 wt% brine. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain crude intermediate I.

[0027] Preferably, the photocatalyst is one of tetraphenylporphyrin, tetra(4-methylphenyl)porphyrin, and (4-chlorophenyl)porphyrin, and the first organic solvent is one of chloroform, dichloromethane, and 1,2-dichloroethane.

[0028] Preferably, after the reaction is complete, the reaction product is washed sequentially with a 1N hydrochloric acid aqueous solution, a 5% sodium bicarbonate aqueous solution, and a 10% saline solution.

[0029] Preferably, step S2 specifically includes:

[0030] The crude intermediate I was added to a second organic solvent, heated and stirred until the solution became clear, then cooled to crystallize, filtered, the filter cake was collected, and dried to obtain the pure intermediate I, which is the key intermediate of galantamine.

[0031] Preferably, the second organic solvent is at least one selected from methanol, ethanol, isopropanol, and n-propanol, and more preferably, methanol.

[0032] Preferably, the ratio of the volume of the second organic solvent to the mass of intermediate II is 2 to 6:1; for example, the ratio is 2:1, 3:1, 4:1, 5:1, 6:1 or any value formed by any two of them, and more preferably, the ratio is 3:1.

[0033] Preferably, the solution heating temperature in step S2 is 50~90℃, for example, 50, 60, 70, 80, 90℃ or any value formed by any two of them, specifically based on the solvent boiling point and the dissolution temperature of the reaction solution; more preferably, it is 65℃.

[0034] Preferably, the cooling and crystallization temperature in step S2 is -5~10℃, for example, -5, 0, 5, 10℃ or any value formed by any two of them, more preferably 0℃.

[0035] Preferably, the low-temperature stirring time in step S2 is 1 to 4 hours, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4 or any value formed by any two of them, specifically based on the condition that there is no significant increase in the precipitation of solids in the solution and stirring is continued for another 0.5 hours; more preferably, it is 2 hours.

[0036] Preferably, step S2 specifically includes:

[0037] The crude intermediate I was added to a second organic solvent and heated and stirred at 50-90°C until the solution became clear. Then the temperature was lowered to -5-10°C and stirred for 1-4 hours to induce crystallization. The crystals were then filtered, the filter cake was collected, and dried to obtain the pure intermediate I, which is the key intermediate of galantamine.

[0038] The beneficial effects of this invention are:

[0039] This invention uses intermediate II as a raw material and, under photocatalysis, utilizes a photocatalytic microchannel reactor with oxygen as the oxidant to oxidize it into intermediate I under light irradiation. The resulting reaction solution is then post-treated to obtain crude intermediate I, which is further purified by recrystallization to obtain pure intermediate I. This method has a series of advantages, including good process stability, excellent reaction selectivity, high yield, and readily available and inexpensive raw materials, simple operation, high safety, and environmental friendliness. Attached Figure Description

[0040] Figure 1 The image shows the H NMR spectrum of intermediate I prepared in Example 1. Detailed Implementation

[0041] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0042] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0043] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0044] Intermediate II in the following examples was purchased from Nanjing Confidi Chemical Technology Co., Ltd., and its structural formula is shown below:

[0045] Example 1

[0046] A method for synthesizing a key intermediate of galantamine via photocatalytic microchannels includes the following steps:

[0047] S1: Add 100 g of intermediate II, 0.97 g of tetraphenylporphyrin, and 3 L of chloroform to a 5 L three-necked flask, and stir until the solution is clear to obtain a reaction solution. Set the temperature of the photocatalytic microchannel reactor to 30 °C, turn on the LED light source, set the light source power to 360 W and the wavelength to 365 nm, turn on the oxygen cylinder, and set the oxygen flow rate to 150 mL / min. Pump the prepared reaction solution into the photocatalytic microchannel reactor at a flow rate of 50 mL / min using a plunger pump, and control the residence time of the reaction solution in the photocatalytic microchannel reactor to 5 min. After the reaction is completed, collect the reaction product and wash it successively with 1 L of 1 N hydrochloric acid solution, 5 wt% sodium bicarbonate solution, and 10 wt% saline solution, dry it, and concentrate it to obtain crude intermediate I.

[0048] S2: Dissolve crude intermediate I in 300 mL of methanol in a 500 mL three-necked flask, heat and stir at 65 °C until the reaction solution is clear, then slowly cool to 0 °C and stir for 2 h, filter, collect the filter cake, dry at 50 °C to obtain 88.2 g of pure intermediate I, which is the final key intermediate product of galantamine, with a yield of 88.7%.

[0049] The H NMR data of the pure intermediate I prepared in this example are as follows: Figure 1 As shown, the H NMR data are as follows:

[0050] 1 H NMR (400 MHz, DMSO): δ 8.12-8.13 (m, 1H), 7.18-7.26 (m, 1H), 7.09-7.13 (m, 1H), 5.98 (d, J =10.3Hz, 1H), 5.43, 5.02 (d, J =15.6, 16.8Hz, 1H), 4.78-4.81(m, 1H), 4.72-4.76, 4.00-4.04(m, 1H), 4.23-4.31(m, 1H), 3.75-3.76(m, 3H), 3.66-3.73, 3.39-3.45(m, 1H), 3.08-3.14(m, 1H), 2.79-2.85(m, 1H), 2.20-2.32(m, 1H), 1.86-1.99(m, 1H). Example 2

[0051] A method for synthesizing a key intermediate of galantamine via photocatalytic microchannels includes the following steps:

[0052] S1: Add 100 g of intermediate II, 1.41 g of tetrakis(4-methylphenyl)porphyrin, and 2.5 L of dichloromethane to a 5 L three-necked flask. Stir until the solution is clear to obtain a reaction solution. Set the temperature of the photocatalytic microchannel reactor to 25 °C, turn on the LED light source, set the light source power to 270 W and the wavelength to 380 nm, turn on the oxygen cylinder, and set the oxygen flow rate to 130 mL / min. Pump the prepared reaction solution into the photocatalytic microchannel reactor at a flow rate of 40 mL / min using a plunger pump, and control the residence time of the reaction solution in the photocatalytic microchannel reactor to 6 min. After the reaction is completed, collect the reaction product and wash it successively with 1 L of 1N hydrochloric acid solution, 5 wt% sodium bicarbonate solution, and 10 wt% brine. Dry and concentrate to obtain crude intermediate I.

[0053] S2: Dissolve crude intermediate I in 250 mL of ethanol in a 500 mL three-necked flask, heat and stir at 75 °C until the reaction solution is clear, then slowly cool to -5 °C and stir for 3 h, filter, collect the filter cake, dry at 50 °C to obtain 85.5 g of pure intermediate I, which is the final key intermediate product of galantamine, with a yield of 86.0%. Example 3

[0054] A method for synthesizing a key intermediate of galantamine via photocatalytic microchannels includes the following steps:

[0055] S1: Add 100 g of intermediate II, 0.99 g of (4-chlorophenyl)porphyrin, and 3.5 L of 1,2-dichloroethane to a 5 L three-necked flask. Stir until the solution is clear to obtain a reaction solution. Set the temperature of the photocatalytic microchannel reactor to 35 °C, turn on the LED light source with a power of 450 W and a wavelength of 340 nm, turn on the oxygen cylinder, and set the oxygen flow rate to 160 mL / min. Pump the prepared reaction solution into the photocatalytic microchannel reactor at a flow rate of 60 mL / min using a plunger pump, controlling the residence time of the reaction solution in the photocatalytic microchannel reactor to be 4 min. After the reaction is complete, collect the reaction product and wash it successively with 1 L of 1N hydrochloric acid solution, 5 wt% sodium bicarbonate solution, and 10 wt% brine. Dry and concentrate to obtain crude intermediate I.

[0056] S2: Dissolve crude intermediate I in 350 mL isopropanol in a 500 mL three-necked flask, heat and stir at 80 °C until the reaction solution is clear, then slowly cool to 5 °C and stir for 2.5 h, filter, collect the filter cake, dry at 50 °C to obtain 83.3 g of pure intermediate I, which is the final key intermediate product of galantamine, with a yield of 83.7%.

[0057] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A method for the synthesis of a key intermediate of galanthamine by photocatalytic microchannel process, characterized by, The method comprises the following steps: S1: using intermediate II as raw material, using a photocatalytic microchannel reactor, using a porphyrin compound as a photocatalyst and oxygen as an oxidant to oxidize under light to generate intermediate I, and obtaining the crude product of intermediate I after treatment; S2: recrystallizing and purifying the obtained crude product of intermediate I to obtain the pure product of intermediate I, that is, the key intermediate of galanthamine; The preparation route of the intermediate I is as follows: ； Step S1 specifically comprises: The intermediate II and the photocatalyst are dissolved in a first organic solvent to obtain a reaction solution, the reaction solution is injected into the photocatalytic microchannel reactor, and oxygen is introduced into the photocatalytic microchannel reactor, and the reaction is carried out under ultraviolet light irradiation, and after the reaction is completed, the crude product of intermediate I is obtained after treatment; The photocatalyst is at least one of tetraphenylporphyrin, tetra(4-methylphenyl)porphyrin, tetra(4-methoxyphenyl)porphyrin and (4-chlorophenyl)porphyrin; The molar ratio of the photocatalyst to the intermediate II is 0.002-0.014:1; The first organic solvent is at least one of dichloromethane, toluene, chloroform and 1,2-dichloroethane, and the volume-to-mass ratio of the first organic solvent to the intermediate II is 10-50:1; In step S1, the reaction solution is injected into the photocatalytic microchannel reactor at a flow rate of 20-80 mL / min, and oxygen is introduced into the photocatalytic microchannel reactor at a flow rate of 100-200 mL / min; In step S1, the wavelength of the ultraviolet light source applied is 300-420 nm, and the power is 180-540 W; In step S1, the temperature of the photocatalytic microchannel reactor is controlled to be 10-30℃, and the residence time of the reaction solution in the photocatalytic microchannel reactor is controlled to be 3-8 min.

2. The method of photocatalytic microchannel synthesis of a key intermediate of galanthamine according to claim 1, characterized in that, Step S1 specifically comprises: The intermediate II and the photocatalyst are dissolved in a first organic solvent to obtain a reaction solution, the reaction solution is injected into the photocatalytic microchannel reactor at a flow rate of 20-80 mL / min, and oxygen is introduced into the photocatalytic microchannel reactor at a flow rate of 100-200 mL / min, the temperature of the photocatalytic microchannel reactor is controlled to be 10-30℃, the ultraviolet light source is turned on, the power of the ultraviolet light source is 180-540 W, the wavelength is 300-420 nm, the residence time of the reaction solution in the photocatalytic microchannel reactor is controlled to be 3-8 min, after the reaction is completed, the reaction product is sequentially washed with 0.5-2N hydrochloric acid solution, 2.5-10wt% sodium bicarbonate solution and 5-20wt% salt water, the organic phase is dried with anhydrous sodium sulfate, concentrated, and the crude product of intermediate I is obtained; The photocatalyst is one of tetraphenylporphyrin, tetra(4-methylphenyl)porphyrin and (4-chlorophenyl)porphyrin, and the first organic solvent is one of chloroform, dichloromethane and 1,2-dichloroethane.

3. The method of photocatalytic microchannel synthesis of a key intermediate of galanthamine according to claim 1, characterized in that, Step S2 specifically comprises: The crude product of intermediate I is added to a second organic solvent, heated and stirred until the solution is clear, then cooled and crystallized, filtered, the filter cake is collected and dried to obtain the pure product of intermediate I, that is, the key intermediate of galanthamine.

4. The method of photocatalytic microchannel synthesis of a key intermediate of galanthamine according to claim 3, characterized in that, Step S2 specifically comprises: The crude intermediate I is added into a second organic solvent, heated and stirred at 50-90℃ until the solution is clear, then cooled to-5-10℃, stirred for 1-4h to crystallize, suction filtered, the filter cake is collected and dried to obtain the pure intermediate I, which is the key intermediate of galanthamine; The second organic solvent is at least one of methanol, ethanol, isopropanol and n-propanol, and the ratio of the volume of the second organic solvent to the mass of the intermediate II is 2-6:1.

Images