Nitrogen-containing bicyclic pyranoside derivatives and methods for their preparation

Abstract

The present application relates to a kind of nitrogen-containing annelated pyranoside derivatives and its preparation method, using D-galactose derivative as raw material, by a kind of efficient and simple and easy to operate photochemical reaction pathway, successfully synthesized with pyrano pyrrolidone structure nitrogen-containing annelated pyranoside derivatives.This method not only widens the selection range of raw material, also greatly simplifies synthesis step, improves synthesis efficiency, provides a kind of new efficient process for the synthesis of pyrano pyrrolidone structure.For the scientific research and technical application of relevant field provide new ideas and means, with significant technical innovation and practical value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a novel nitrogen-containing fused pyranose glycoside derivative and a preparation method thereof. BACKGROUND

[0002] Tetrahydropyran ring (THP for short) as an important organic compound structure has wide application and significant importance in the field of medicine. Its unique chemical properties and biological activities make it a key component in the structure of various drug molecules. Tetrahydropyran ring has a low entropy and a rigid cyclic structure, which can increase the contact points with the target by providing oxygen atoms as hydrogen bond acceptors, thereby enhancing the binding ability of the drug to the receptors in the body. In medicinal chemistry, the THP substituent 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 on the market and in development contain tetrahydropyran ring structure. For example, some drugs for treating diabetes and cardiovascular diseases contain tetrahydropyran ring in their active ingredients. Through the special structure of the tetrahydropyran ring, these drugs achieve precise recognition and efficient action on disease targets, thereby showing significant therapeutic effect in the treatment process.

[0003] Pyrrolidone ring, as a molecular structure with unique chemical properties and a wide range of biological activities, plays a crucial 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 physicochemical properties and biological activities, making pyrrolidone ring a core component in the structure of many drug molecules. In drug development, pyrrolidone ring is widely used due to its ability to enhance drug solubility, improve drug affinity to receptors in the body, and optimize drug metabolic characteristics. Many drugs that have been marketed or are in clinical trials contain pyrrolidone ring structures. For example, in the field of antibiotics, some compounds based on pyrrolidone ring have been shown to effectively inhibit the growth and reproduction of bacteria, thus demonstrating significant efficacy in the treatment of infectious diseases. These drugs achieve antibacterial effects by interfering with and disrupting key life processes such as bacterial cell wall synthesis and DNA replication through the special mechanism of pyrrolidone ring. In addition, in the field of central nervous system drugs, pyrrolidone ring is also widely used. Some drugs containing pyrrolidone ring can regulate the release and transmission of neurotransmitters, thus playing an important role in the treatment of mental illnesses, neurodegenerative diseases, and other aspects. These drugs improve the function of the nervous system, alleviate the symptoms of patients, and improve the quality of life. 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 pyrrolidone ring.

[0004] Although both of these organic compound structural units have important significance in the field of drug synthesis, the combination of the two to form a fused ring structure is not common, and there is a lack of effective synthesis methods to prepare such fused ring structures. In nature, the tetrahydropyran ring structure exists in the pyranoside structure, and how to use the abundant pyranoside material to prepare tetrahydropyran ring and pyrrolidone ring is an important challenge in the field. SUMMARY

[0005] To solve the above technical problems existing in the prior art, the present application provides a nitrogen-containing fused pyranoside derivative and a preparation method thereof.

[0006] In a first aspect of the present application, a nitrogen-containing fused pyranoside derivative is provided, which has the following formula (I) or formula (II) structure general formula:

[0007]

[0008] wherein, R1, R2, R3, R4 are the same or different substituents, independently selected from one of CH3O-, CH3OCH2-, BnO-, BnOCH2-, CH3CH2O- and CH3CH2OCH2-; R5 is aryl. The chemical structure of the general formula of the above formula (I) or formula (II) shows a bicyclic fused ring structure formed by directly fusing a tetrahydropyran ring and a pyrrolidone ring. Such a molecular structure has very important potential application value in the field of pharmacy. On the other hand, it should also be noted that there are two fluorine atoms on the pyrrolidone ring. Fluorine atoms have smaller atomic radii and higher electronegativity, which enables them to bind closely to receptors or other biological molecules, thereby enhancing the interaction of the drug with the target. By changing the electronic distribution of the drug molecule, the fluorine atom can affect the conformation and stability of the drug, thereby improving its biological activity, and thus further improving the application prospect of the fused ring structure in the pharmaceutical field.

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

[0010] Another aspect of the present application is to provide a preparation method of a nitrogen and ring pyranoside derivative, comprising the following steps:

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

[0012] (2) adding a certain amount of organic solvent into the photochemical reaction container so as 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) so that the reaction occurs;

[0014] (4) after a certain time of reaction, stopping the irradiation of the light source, and obtaining a compound of formula (I) or formula (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 compound of formula (III) and formula (IV) can be prepared by using D-galactal as a raw material. Therefore, the present application makes full use of the pyran ring structure in D-galactal to directly fuse with the pyrrolidone ring through photochemical reaction to obtain the compound of formula (I) and formula (II).

[0017] In the preferred scheme, when the equivalent of the compound of formula (III) or formula (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 the preferred scheme, the organic solvent added in step (2) is selected from one of acetonitrile and acetone. It is found through experiments that other common solvents have poor effects on the reaction.

[0019] In the preferred scheme, a pair of blue light lamps are arranged outside the photochemical reaction container in a mutual contrast manner, the power of a single blue light lamp is 20 W, and the wavelength of the blue light is 456 nm. In the reaction, the light density in the reaction solution can be effectively improved by arranging the contrast blue light lamps, and the reaction efficiency of the photochemical reaction in the application can be improved.

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

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

[0022] The beneficial technical effects of the application are that the application successfully synthesizes the nitrogen-containing pyrano pyrrolidone derivative by using D-galactonic acid derivative as the raw material and through an innovative and simple photochemical reaction route. This method not only widens the selection range of the raw material, but also greatly simplifies the synthesis steps and improves the synthesis efficiency, thereby providing a new and efficient process for the synthesis of pyrano pyrrolidone structure. The application provides a new idea and means for scientific research and technical application in the related field, and has significant technical innovation and practical value.

[0023] Drawings of the specification

[0024] Figure Figure 1 is the reaction route diagram of the application.

[0025] Figure Figure 2 is the H nuclear magnetic resonance spectrum of the target product of Example 1.

[0026] Figure Figure 3 is the C nuclear magnetic resonance spectrum of the target product of Example 1.

[0027] Figure Figure 4 is the F nuclear magnetic resonance spectrum of the target product of Example 1. DETAILED DESCRIPTION

[0028] The application will be further described below in combination with the drawings and specific implementation methods.

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

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

[0031] Example 1

[0032] 0.1 mmol of 3,4,6-trio-benzylgalactal (CAS: 80040-79-5) was added to the reaction flask. Then, 0.15 mmol 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-trio-benzylgalactalactal), 0.15 mmol of Li2CO3, and 10 mol% of NH4Cl were added to the flask. Under nitrogen protection, 1 mL of acetonitrile was injected into the flask using a syringe. The reaction was carried out under stirring at room temperature with two 20W blue lamps (456 nm) for illumination. The blue lamps were turned off on both sides of the reaction flask for comparison. After 48 hours of reaction, the blue lamp illumination was stopped, and the reaction solution was distilled under reduced pressure to obtain a mixture. The mixture was then separated by silica gel column chromatography to obtain the target compound in 70% yield. Figures 2-4 The H NMR spectrum, C NMR spectrum, and F NMR spectrum of the target compound are displayed separately. The molecular formula and structure of the target compound can be confirmed by 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] As demonstrated in Examples 1-4, the highest yield can be obtained at a reaction time of 48 hours. Further extending the reaction time does not increase the yield; in fact, it decreases it. A yield of 60.8% can be obtained at 24 hours, and even with half the reaction time, the yield is 87% of the maximum yield. Therefore, depending on the actual situation, controlling the reaction time within 24-48 hours will yield the ideal yield.

[0041] Example 5

[0042] The operation is the same as in Example 1, except that a single blue light lamp is set, which is set to 40W with a wavelength of 456nm and a yield of 31.3%.

[0043] Example 6

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

[0045] Example 7

[0046] The operation is the same as in Example 1, except that a single blue light lamp is set, which is set to 20W, with a wavelength of 456nm and a yield of 16.1%.

[0047] Example 8

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

[0049] As can be seen from Examples 1 and 5-8, setting a control blue light lamp can effectively increase the light intensity in the reaction vessel, 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 to 2×10W with a wavelength of 456nm and a yield of 40.7%.

[0052] Example 10

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

[0054] Example 11

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

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

[0057] Example 12

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

[0059] Example 13

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

[0061] Example 14

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

[0063] Example 15

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

[0065] As can be seen from Examples 1 and 12-15, 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 procedure is the same as in Example 1, except that 2-bromo-2,2-difluoro-N-(p-tolyl)acetamide is used instead of 2-bromo-2,2-difluoro-N-phenylacetamide in Example 1. The structural formula of the target product is as follows: The yield was 58%.

[0068] Example 17

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

[0070] Example 18

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

[0072] Example 19

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

[0074] Example 20

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

[0076] Example 21

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

[0078] Example 22

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

[0080] Example 23

[0081] The procedure is the same as in Example 1, except that 3,4,6-trio-methylgalactal is used instead of 3,4,6-trio-benzylgalactal in Example 1. The structural formula of the target product obtained is as follows: The yield was 35%.

[0082] Example 24

[0083] The procedure is the same as in Example 1, except that 3,4,6-tri-o-ethylgalactal is used instead of 3,4,6-tri-o-benzylgalactal in Example 1. The structural formula of the target product obtained is as follows: The yield was 31%.

[0084] Example 25

[0085] The procedure is the same as in Example 1, except that 3-O-benzyl-4,6-O-isopropylidene-D-glucuronide is used instead of 3,4,6-tri-o-benzylgalactal in Example 1. The structural formula of the target product obtained is as follows: The yield was 31%.

[0086] Comparative Example 1

[0087] The paper "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 showed that this catalyst is difficult to use in reaction with glycoside derivatives to generate tetrahydropyran ring and pyrrolidone ring fused structure compounds synthesized in this application. The specific synthesis process is shown below.

[0088] Add 0.1 mmol of 3,4,6-tri-o-benzylgalactal to the light reaction flask, then add 0.2 mmol of 2-bromo-2,2-difluoro-N-phenylacetamide, CNNs-3 (5 mg), and LiO2 to the reaction flask. t Bu (0.15 mmol). Under inert gas protection, 1.5 mL of acetonitrile was injected into the bottle using a syringe; the reaction was carried out at room temperature with stirring for 12 hours under irradiation by two 20W blue lamps (456 nm), and no target product was detected. This indicates that although the above literature discloses a method for synthesizing pyrrolidone, its catalytic system is not suitable for 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 involves the photocatalyst Ir(ppy)2(dtbbpy)PF6 being excited under blue light irradiation. This excitation process removes the bromide anion from the 2-bromo-2,2-difluoro-N-phenylacetamide substrate, generating a difluoroalkyl radical, which then adds to the glycoside to form an intermediate. Nucleophilic attack is performed on the amine under alkaline conditions to obtain the final target product.

[0090] The technical solutions provided by the present invention have been described in detail above. For those skilled in the art, there will be changes in specific implementation methods and application scope based on the ideas of the embodiments of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A process for the preparation of a nitrogen-containing homo- pyranoside derivative, characterized in that, The method comprises the following steps: (1) adding a compound of formula (III), a compound of formula (V), Ir(ppy)2(dtbbpy)PF6, Li2CO3 and NH4Cl into a photochemical reaction vessel; (2) adding a certain amount of an organic solvent into the photochemical reaction vessel so that the reactants added in step (1) are dissolved; (3) setting up a light source outside the photochemical reaction vessel to irradiate the solution in step (2) so that the reaction occurs; (4) stopping the irradiation of the light source after a certain time, and obtaining the compound of formula (I) through separation and purification; ； wherein R1 is selected from one of CH3OCH2-, BnOCH2- and CH3CH2OCH2-; R2 and R3 are independently selected from one of CH3O-, BnO- and CH3CH2O-; R5is selected from the group consisting of wherein R6is selected from one of H, CH3-, CH3O-, Cl, Br, CF3O-, and CH3S-. wherein the organic solvent added in step (2) is selected from one of acetonitrile and acetone.

2. The method for preparing the nitrogen-containing cyclopyranoside derivative as described in claim 1, characterized in that, The equivalent of the compound of formula (III) added in step (1) is 1, and 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.

3. The method of producing a nitrogen-containing homoallylic pyranoside derivative according to claim 1, wherein A pair of blue light lamps are set up outside the photochemical reaction vessel, and the power of a single blue light lamp is 20-30 W, and the wavelength of the blue light is 456 nm.

4. The method for preparing the nitrogen-containing cyclopyranoside derivative as described in claim 1, characterized in that, The reaction time in step (3) is 24-48 hours.

5. The method for preparing the nitrogen-containing cyclopyranoside derivative as described in claim 1, characterized in that, The separation operation in step (4) comprises removing the reaction solvent through reduced pressure distillation, and then separating the compound of formula (I) through silica gel column chromatography.

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