Nitrogen-containing ring-fused pyranoside derivative and preparation method thereof

Abstract

The invention relates to a nitrogen-containing ring-fused pyranoside derivative and a preparation method thereof, and the nitrogen-containing ring-fused pyranoside derivative with a pyranopyrrolidone structure is successfully synthesized by taking a D-galactaldehyde derivative as a raw material through an efficient, simple and feasible photochemical reaction way. According to the method, the selection range of the raw materials is widened, the synthesis steps are greatly simplified, the synthesis efficiency is improved, and a brand new efficient process is provided for synthesis of a pyranopyrrolidone structure. The method provides a new thought and means for scientific research and technical application in related fields, and has remarkable technical innovation and practical value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a novel nitrogen-containing cyclic pyranoside derivative and a preparation method thereof. Background Art

[0002] As an important organic compound structure, tetrahydropyran ring (THP) has wide applications and significant importance in the field of medicine. Its unique chemical properties and biological activity make it a key component in the molecular structure of many drugs. The tetrahydropyran ring has low entropy and a rigid ring structure. It can provide oxygen atoms as hydrogen bond receptors to increase the contact points with the target, thereby enhancing the binding ability of the drug to the receptor in the body. In medicinal chemistry, THP replaces its lower lipophilicity and is widely used to adjust the pKa value of the drug and improve the absorption, distribution, metabolism and excretion (ADME) characteristics of the drug. Many drugs that have been marketed and are under development contain tetrahydropyran ring structures. For example, some drugs used to treat diabetes and cardiovascular diseases contain tetrahydropyran rings in their active ingredients. This type of drug achieves accurate identification and efficient action on disease targets through the special structure of the tetrahydropyran ring, thereby showing significant therapeutic effects during the treatment process.

[0003] Pyrrolidone ring, as a molecular structure with unique chemical properties and extensive biological activity, plays a vital role in the field of medicine. Its stable five-membered ring structure, combined with the presence of nitrogen atoms and carbonyl groups, endows drug molecules with special physical and chemical properties and biological activities, making the pyrrolidone structure a core component of many drug molecular structures. In drug research and development, the pyrrolidone structure is widely used because it can enhance the solubility of drugs, improve the affinity of drugs with receptors in the body, and optimize the metabolic characteristics of drugs. Pyrrolidone structure can be seen in many drugs that have been marketed or are in clinical trials. For example, in the field of antibiotics, some compounds based on pyrrolidone structure have been shown to effectively inhibit the growth and reproduction of bacteria, thereby showing significant therapeutic effects in the treatment of infectious diseases. These drugs achieve the purpose of antibacterial by interfering with and destroying key life processes such as bacterial cell wall synthesis and DNA replication through the special mechanism of action of the pyrrolidone structure. In addition, the pyrrolidone structure is also widely used in central nervous system drugs. Some drugs containing pyrrolidone structures can regulate the release and transmission of neurotransmitters, thus playing an important role in the treatment of mental illness, neurodegenerative diseases, etc. These drugs relieve patients' symptoms and improve their quality of life by improving the function of the nervous system. The paper "Engineered Polymeric Carbon Nitride for Photocatalytic Diverse Functionalization of Electronic-Rich Alkenes" reports a carbon-nitrogen nanomaterial CNNs-3, and uses this nanomaterial as a catalyst to synthesize a pyrrolidone structure.

[0004] Although these two organic compound structural units are of great significance in the field of drug synthesis, it is rare for them to combine to form a fused ring structure, and there is a lack of effective synthetic means to prepare such a fused ring structure. In nature, the tetrahydropyran ring structure exists in the pyranoside structure. How to use the abundant pyranoside substances to prepare the tetrahydropyranoside ring and pyrrolidone structure is an important challenge in this field. Summary of the invention

[0005] In order to solve the above technical problems existing in the prior art, the present invention provides a nitrogen-containing cyclic pyranoside derivative and a preparation method thereof.

[0006] In the first aspect of the present invention, there is provided a nitrogen-containing cyclic pyranoside derivative having the following general structural formula (I) or (II):

[0007]

[0008] Wherein, R1, R2, R3, R4 are identical or different substituents, independently selected from one of CH3O-, CH3OCH2-, BnO-, BnOCH2-, CH3CH2O- and CH3CH2OCH2-; R5 is an aromatic group. The chemical structures shown in the general structural formula of the above formula (I) or formula (II) all have a bicyclic fused ring structure formed by the direct fusion of a tetrahydropyran ring and a pyrrolidone ring. This molecular structure has very important potential application value in the pharmaceutical field. On the other hand, it should also be noted that there are two fluorine atoms on the pyrrolidone ring. The fluorine atom has a smaller atomic radius and a higher electronegativity, which enables it to bind tightly to receptors or other biological molecules, thereby enhancing the interaction between the drug and the target. By changing the electron distribution of the drug molecule, the fluorine atom can affect the conformation and stability of the drug, thereby improving its biological activity, thereby further improving the application prospects of the fused ring structure in the pharmaceutical field.

[0009] In a preferred embodiment, R5 is Wherein, R6 is selected from one of H, CH3-, CH3O-, Cl, Br, CF3O- and CH3S-.

[0010] Another aspect of the present invention is to provide a method for preparing an azopyranoside derivative, comprising the following steps:

[0011] (1) Adding a compound of formula (III) or (IV), a compound of formula (V), Ir(ppy)2(dtbbpy)PF6, Li2CO3 and NH4Cl into a photochemical reaction vessel;

[0012] (2) adding a certain amount of organic solvent into the photochemical reaction vessel to dissolve the reactants added in step (1);

[0013] (3) setting up a light source outside the photochemical reaction container to irradiate the solution in step (2) to cause a reaction;

[0014] (4) After a certain reaction time, stop irradiating with the light source, and obtain the compound of formula (I) or (II) through separation and purification, wherein when the compound of formula (III) is added in step (1), the compound of formula (I) is obtained, and when the compound of formula (IV) is added in step (1), the compound of formula (II) is obtained;

[0015]

[0016] As can be seen from the above formula, the compounds of formula (III) and formula (IV) can be prepared by using D-galactaldehyde as a raw material. Therefore, the present invention makes full use of the pyran ring structure in D-galactaldehyde to directly condense it with the pyrrolidone ring through a photochemical reaction to obtain the compounds of formula (I) and formula (II).

[0017] In a preferred embodiment, when the equivalent of the compound of formula (III) or (IV) added in step (1) is 1, the equivalents of the compound of formula (V), Ir(ppy)2(dtbbpy)PF6, Li2CO3 and NH4Cl added are 1-1.5, 0.01-0.02, 1-2 and 0.05-0.2 respectively.

[0018] In a preferred embodiment, the organic solvent added in step (2) is selected from acetonitrile and acetone. It has been found through experiments that other common solvents have poor effects on the reaction.

[0019] In a preferred embodiment, a pair of blue light lamps are set outside the photochemical reaction container in a contrasting manner, the power of a single blue light lamp is 20 W, and the wavelength of the blue light is 456 nm. In this reaction, by setting the contrasting blue light lamp, the optical density in the reaction solution can be effectively increased, thereby improving the reaction efficiency of the photochemical reaction in the present invention.

[0020] In a preferred embodiment, the reaction time in step (3) is 24-48 hours.

[0021] In a preferred embodiment, the separation operation in step (4) comprises removing the reaction solvent by distillation under reduced pressure, and then separating and purifying by silica gel column chromatography to obtain the compound of formula (I) or formula (II).

[0022] The beneficial technical effect of the present invention is that, for the first time, the present invention uses D-galactaldehyde derivatives as raw materials and successfully synthesizes nitrogen-containing cyclic pyranoside derivatives through an innovative and simple photochemical reaction pathway. This method not only broadens the selection range of raw materials, but also greatly simplifies the synthesis steps and improves the synthesis efficiency, providing a new and efficient process for the synthesis of pyranopyrrolidone structures. It provides new ideas and means for scientific research and technical applications in related fields, and has significant technical innovation and practical value.

[0023] Instruction Manual

[0024] Attached Figure 1 It is the reaction scheme of the present invention.

[0025] Attached Figure 2 It is the H NMR spectrum of the target product of Example 1.

[0026] Attached Figure 3 It is the C NMR spectrum of the target product in Example 1.

[0027] Attached Figure 4 It is the F NMR spectrum of the target product in Example 1. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with the accompanying drawings and specific implementation methods.

[0029] The preparation process of 3,4,6-tri-o-benzylgalactaldehyde is as follows: 10 mmol of -galactaldehyde is pre-dried under vacuum for 1 hour, then dissolved in 20 mL of anhydrous N,N-dimethylformamide, cooled to 0°C, 62 mmol of NaH is slowly added in batches to the above N,N-dimethylformamide solution containing D-galactaldehyde, stirred at room temperature for 30 minutes, and then the mixture is cooled to 0°C, and 40 mmol of benzyl bromide is added dropwise. The solution is then stirred at room temperature for 18 hours, and then the reaction is quenched with 5 mL of methanol, and the solvent is rotary evaporated to obtain a solid mixture. The obtained solid mixture is dissolved in 30 mL of dichloromethane, then washed with 30 mL of water, and then washed with 30 mL of saturated brine, the organic phase is collected and dried with anhydrous magnesium sulfate, and then dried under reduced pressure and separated by column chromatography to obtain the target compound 3,4,6-tri-o-benzylgalactaldehyde, whose structural formula is

[0030] The preparation process of 3,4,6-tri-o-methylgalactaldehyde is as follows: 10 mmol of D-galactaldehyde is pre-dried under vacuum for 1 hour, and then dissolved in 20 mL of anhydrous N,N-dimethylformamide and cooled to 0°C. 62 mmol of NaH is slowly added in batches to the above N,N-dimethylformamide solution containing D-galactaldehyde, stirred at room temperature for 30 minutes, and then the mixture is cooled to 0°C and 50 mmol of MeI is added dropwise. The solution is then stirred at room temperature for 18 hours, and then the reaction is quenched with 10 mL of methanol, and the solvent is rotary evaporated to obtain a solid mixture. The obtained solid mixture is dissolved in 30 mL of dichloromethane, then washed with 30 mL of water, and then washed with 30 mL of saturated brine. The organic phase is collected and dried with anhydrous magnesium sulfate, and then dried under reduced pressure and separated by column chromatography to obtain the target compound 3,4,6-tri-o-methylgalactaldehyde, whose structural formula is

[0031] Example 1

[0032] Add 0.1mmol of 3,4,6-tri-o-benzylgalactaldehyde (CAS: 80040-79-5) to the photoreaction bottle, and then add 0.15mmol of 2-bromo-2,2-difluoro-N-phenylacetamide (CAS: 127427-45-6), 1.5 mol% of Ir(ppy)2(dtbbpy)PF6 (based on the amount of 3,4,6-tri-o-benzylgalactaldehyde), Li2CO3 (0.15mmol), and NH4Cl (10mol%) to the reaction bottle. Under the protection of nitrogen gas, inject 1mL of acetonitrile into the bottle with a syringe; stir the reaction at room temperature under the irradiation of two 20W blue light lamps (456nm), and turn off the blue light on both sides of the photoreaction bottle for mutual reference. After reacting for 48 hours, stop irradiating the blue light, distill the reaction solution under reduced pressure to obtain a mixture, and separate the obtained mixture by silica gel column chromatography to obtain the target compound with a yield of 70%. Figure 2-4 The H NMR spectrum, C NMR spectrum and F NMR spectrum of the target compound are displayed respectively, and the molecular formula structure of the target compound can be confirmed through the above spectra.

[0033]

[0034] Example 2

[0035] The operation was the same as in Example 1, except that the reaction time was set at 12 hours and the yield was 41.3%.

[0036] Example 3

[0037] The operation was the same as in Example 1, except that the reaction time was set at 24 hours, and the yield was 60.8%.

[0038] Example 4

[0039] The operation was the same as in Example 1, except that the reaction time was set at 72 hours and the yield was 64.3%.

[0040] It can be seen from Examples 1-4 that the highest yield can be obtained at a reaction time of 48 hours, and further extension of the reaction time cannot increase the yield, but rather decreases it. A higher yield of 60.8% can be obtained at 24 hours, and the yield value of the maximum yield is 87% of the reaction time, which can be obtained by controlling the reaction time to 24-48 hours according to actual conditions.

[0041] Example 5

[0042] The operation was the same as in Example 1, except that a single blue light lamp was provided, the blue light lamp was set at 40 W, the wavelength was 456 nm, and the yield was 31.3%.

[0043] Example 6

[0044] The operation is the same as in Example 1, except that a single blue light lamp is provided, the blue light lamp is set at 30 W, the wavelength is 456 nm, and the yield is 24.6%.

[0045] Example 7

[0046] The operation was the same as in Example 1, except that a single blue light lamp was provided, the blue light lamp was set at 20 W, the wavelength was 456 nm, and the yield was 16.1%.

[0047] Example 8

[0048] The operation was the same as in Example 1, except that the reaction blue light lamp was set at 10 W, the wavelength was 456 nm, and the yield was very low.

[0049] It can be seen from Examples 1 and 5-8 that the light intensity in the reaction container can be effectively increased by providing a control blue light lamp, thereby improving the reaction efficiency.

[0050] Example 9

[0051] The operation was the same as in Example 1, except that the reaction blue light lamp was set at 2×10 W, the wavelength was 456 nm, and the yield was 40.7%.

[0052] Example 10

[0053] The operation was the same as in Example 1, except that the reaction blue light lamp was set at 2×30 W, the wavelength was 456 nm, and the yield was 65.1%.

[0054] Embodiment 11

[0055] The operation was the same as in Example 1, except that the reaction blue light lamp was set at 2×40 W, the wavelength was 456 nm, and the yield was 60.3%.

[0056] It can be seen from Examples 1 and 9-11 that the power of the blue light lamp has a strong influence on the reaction. When two blue light lamps are used for comparison, a single blue light lamp with a power of 20-30W can obtain a better yield. Otherwise, too high or too low a yield will damage the final yield data.

[0057] Example 12

[0058] The operation was the same as in Example 1, except that the reaction solvent was acetone, and the yield was 28.3%.

[0059] Embodiment 13

[0060] The operation was the same as in Example 1, except that the reaction solvent was N,N-dimethylformamide. The yield was 8.1%.

[0061] Embodiment 14

[0062] The operation was the same as in Example 1, except that the reaction solvent was dichloromethane and the yield was 0.

[0063] Embodiment 15

[0064] The operation is the same as in Example 1, except that the reaction solvent is tetrahydrofuran and the yield is extremely low.

[0065] It can be seen from Examples 1 and 12-15 that dichloromethane is a good solvent for this reaction, followed by acetone, while other solvents are not easy to obtain ideal yields.

[0066] Example 16

[0067] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 58%.

[0068] Embodiment 17

[0069] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-methoxyphenyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 55%.

[0070] Embodiment 18

[0071] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-chlorophenyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 71%.

[0072] Embodiment 19

[0073] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-bromophenyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 67%.

[0074] Embodiment 20

[0075] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-trifluoromethoxyphenyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 60%.

[0076] Embodiment 21

[0077] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(m-tolyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 58%.

[0078] Embodiment 22

[0079] The operation is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(m-methylthiophenyl)acetamide is used to replace 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1, and the structural formula of the obtained target product is The yield was 60%.

[0080] Embodiment 23

[0081] The operation is the same as in Example 1, except that 3,4,6-tri-o-methylgalactaldehyde is used to replace 3,4,6-tri-o-benzylgalactaldehyde in Example 1, and the structural formula of the obtained target product is The yield was 35%.

[0082] Embodiment 24

[0083] The operation is the same as in Example 1, except that 3,4,6-tri-o-ethylgalactaldehyde is used to replace 3,4,6-tri-o-benzylgalactaldehyde in Example 1, and the structural formula of the obtained target product is The yield was 31%.

[0084] Embodiment 25

[0085] The operation is the same as in Example 1, except that 3-O-benzyl-4,6-O-isopropylidene-D-glucuronide is used to replace 3,4,6-tri-o-benzylgalactaldehyde in Example 1, and the structural formula of the obtained target product is The yield was 31%.

[0086] Comparative Example 1

[0087] The document "Engineered Polymeric Carbon Nitride for Photocatalytic Diverse Functionalization of Electronic-Rich Alkenes" discloses a nano carbon nitrogen catalyst that can be used for the synthesis of pyrrolidone rings. The nano carbon nitrogen catalyst is CNNs-3. Experiments have shown that the catalyst is difficult to react with glycoside derivatives to produce tetrahydropyran ring and pyrrolidone ring fused structure compounds synthesized in this application. The specific synthesis process is shown below.

[0088] 3,4,6-tri-o-benzylgalactaldehyde (0.1 mmol) was added to the photoreaction bottle, and then 2-bromo-2,2-difluoro-N-phenylacetamide (0.2 mmol), CNNs-3 (5 mg), LiO t Bu (0.15mmol). Under the protection of inert gas, 1.5mL of acetonitrile was injected into the bottle with a syringe; the reaction was stirred at room temperature for 12 hours under the irradiation of two 20W blue light lamps (456nm), and no target product was detected. Although the above document discloses a method for synthesizing pyrrolidone, its catalytic system cannot be adapted to glycoside compounds, that is, it cannot be used to synthesize the nitrogen-containing cyclopyranoside derivatives involved in this patent.

[0089] Further research revealed that the possible mechanism of the reaction is that the photocatalyst Ir(ppy)2(dtbbpy)PF6 becomes excited under blue light, removes the bromine anion from the substrate 2-bromo-2,2-difluoro-N-phenylacetamide, generates difluoroalkyl free radicals, and then adds them to the glycoside to form an intermediate. Under alkaline conditions, the amine undergoes a nucleophilic attack to give the final target product.

[0090] The technical solution provided by the present invention is introduced in detail above. For those skilled in the art, according to the concept of the embodiments of the present invention, there may be changes in the specific implementation method and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A nitrogen-containing cyclic pyranoside derivative, characterized in that: It is a compound having the following general structural formula (I) or (II), wherein R1, R2, R3, and R4 are identical or different substituents, independently selected from one of CH3O-, CH3OCH2-, BnO-, BnOCH2-, CH3CH2O-, and CH3CH2OCH2-; Wherein, R5 is an aryl group.

2. The nitrogen-containing cyclopyranoside derivative according to claim 1, characterized in that R5 is Wherein, R6 is selected from one of H, CH3-, CH3O-, Cl, Br, CF3O- and CH3S-.

3. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 1-2, characterized in that: The following steps are involved: (1) Adding a compound of formula (III) or (IV), a compound of formula (V), Ir(ppy)2(dtbbpy)PF6, Li2CO3 and NH4Cl into a photochemical reaction vessel; (2) adding a certain amount of organic solvent into the photochemical reaction vessel to dissolve the reactants added in step (1); (3) setting up a light source outside the photochemical reaction container to irradiate the solution in step (2) to cause a reaction; (4) After a certain reaction time, stop irradiating with the light source, and obtain the compound of formula (I) or (II) through separation and purification, wherein when the compound of formula (III) is added in step (1), the compound of formula (I) is obtained, and when the compound of formula (IV) is added in step (1), the compound of formula (II) is obtained; 4. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 3, characterized in that: When the equivalent of the compound of formula (III) or (IV) added in step (1) is 1, the equivalents of the compound of formula (V), Ir(ppy)2(dtbbpy)PF6, Li2CO3 and NH4Cl added are 1-1.5, 0.01-0.02, 1-2 and 0.05-0.2 respectively.

5. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 3, characterized in that: The organic solvent added in step (2) is selected from one of acetonitrile and acetone.

6. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 3, characterized in that: A pair of blue light lamps set in contrast to each other are set outside the photochemical reaction container, the power of a single blue light lamp is 20-30W, and the wavelength of the blue light is 456nm.

7. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 3, characterized in that: The reaction time in step (3) is 24-48 hours.

8. The method for preparing the nitrogen-containing cyclopyranoside derivative according to claim 3, characterized in that: The separation operation in step (4) comprises removing the reaction solvent by distillation under reduced pressure, and then separating by silica gel column chromatography to obtain the compound of formula (I) or formula (II).

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