A method for preparing a compound containing a chiral pyrrole skeleton

Abstract

The present application relates to the technical field of pyrrole derivative preparation, in particular to a green preparation method of a compound containing a chiral pyrrole skeleton, and specifically to an L-phenylalanine template compound, which is reacted with 2,5-dimethoxytetrahydrofuran (DMTHF) to obtain a pyrrole derivative directly in water as a green solvent with a high yield, and the scheme is expanded, and an equivalent and easy-to-prepare substitute 1,4-butanediol of DMTHF is used as a starting material and is reacted with L-phenylalaninol to obtain a corresponding amino alcohol pyrrole derivative in a nearly complete quantitative conversion, and the method has the advantages of mild reaction conditions, a green solvent as a reaction medium, nearly complete quantitative conversion, a chiral center configuration maintained, and easy amplification.

Description

Technical Field

[0001] This invention relates to the field of pyrrole derivative preparation technology, and specifically to a green preparation method for compounds containing a chiral pyrrole skeleton. Background Technology

[0002] Pyrrole derivatives often exhibit significant biological activity. As important intermediates in natural products and heterocyclic compounds, such as vitamin B12, bile pigments, heme, chlorophyll, and alkaloids, they all contain pyrrole fragments. Many synthesized compounds containing pyrrole rings show certain antibacterial, antiviral, and antitumor biological activities. Pyrrole derivatives with chiral substitution at the nitrogen atom often exhibit important biological activities. Therefore, pyrrole is a highly promising unit in derivatization modifications and alterations that are closely related to its activity.

[0003] Pyrrole units have long been a focus of attention in the fields of peptide mimics, natural products, and heterocyclic compounds as active fragments. In recent years, numerous Paal-Knorr cyclization reactions of primary amines and 1,4-diketones catalyzed by Lewis acids, such as Ti(Oi-Pr)4, ZrOCl2·8H2O, Sc(OTf)3, Bi(NO3)3·5H2O, ZrCl4, BiCl3 / SiO2, InCl3, and FeCl3, have been reported. However, most of these methods have certain drawbacks, such as harsh reaction conditions, poor substrate suitability, and a tendency for substitution side reactions to occur on the heterocyclic core. Therefore, there is an urgent need to explore a mild, efficient, and highly selective reaction method for the synthesis of N-substituted pyrrole derivatives.

[0004] Pyrrole-protected chiral amino acids and amino alcohols and their derivatives have wide applications in chemistry, biology, and pharmaceuticals. These optically pure primary amines often present solubility challenges in conventional solvents. Furthermore, due to the epimerization of the chiral center, pyrrole protection typically requires a two-phase system of immiscible water / halogenated organic solvent. This involves acid catalysis under heating conditions to generate pyrrole derivatives while simultaneously extracting the organic phase to reduce or avoid epimerization of the chiral center.

[0005] However, using traditional acid / base buffer systems results in low yields, excessive time consumption, and the products generally require cumbersome column chromatography purification. Summary of the Invention

[0006] In view of the above, this application provides a green preparation method for compounds containing a chiral pyrrole skeleton. This method has the advantages of mild reaction conditions, green solvent as reaction medium, near-quantitative complete conversion, preservation of chiral center configuration, and easy scale-up.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A green method for preparing compounds containing a chiral pyrrole skeleton, the method comprising the following steps:

[0009] Take a reaction flask, place a magnetic stir bar inside, dissolve L-phenylalanine / L-phenylalanine in pure water to obtain the template substrate, put it into the reaction flask, and slowly add the γ-dicarbonyl compound or its equivalent dropwise using a pipette. After sealing, heat to 90-100℃ and react for 0.5-4 hours. After the reaction, cool the product to room temperature, and then centrifuge at 8000 r / min for 4-6 min. Dissolve the centrifuged product in a solvent and wash it with water. Then dry the organic phase with anhydrous sodium sulfate and remove the solvent using a rotary evaporator to obtain the crude pyrrole protected product, which is the finished pyrrole derivative (a compound containing a chiral pyrrole skeleton).

[0010] In this invention, the reaction flask is a capped reaction flask with a volume of 5 ml.

[0011] In this invention, the solvent is further described as ethyl acetate or chloroform.

[0012] In this invention, the template substrate is obtained by dissolving L-phenylalanine in pure water.

[0013] In this invention, the γ-dicarbonyl compound or its equivalent is 2,5-dimethoxytetrahydrofuran.

[0014] In this invention, the template substrate is obtained by dissolving L-phenylalanine in pure water.

[0015] In this invention, the γ-dicarbonyl compound or its equivalent is an aqueous solution of 1,4-butanedialdehyde.

[0016] In this invention, the 1,4-butanedialdehyde aqueous solution is obtained by the following method: 2,5-dimethoxytetrahydrofuran is dissolved in pure water, 10wt% Amberlyst-732 resin is added as a catalyst, the temperature is raised to 70°C, the methanol produced is evaporated in an open container, after 3.5-4.5 hours, the mixture is cooled to room temperature, and then the resin is removed by filtration to obtain the 1,4-butanedialdehyde aqueous solution for later use.

[0017] In this invention, the pH of the 1,4-butanedialdehyde aqueous solution is further defined as 6.5-7.

[0018] The pure water specifically refers to ultrapure water.

[0019] The present invention has at least the following beneficial effects:

[0020] This invention uses pure aqueous phase as a medium, with mild reaction conditions, preservation of chiral center configuration, and easy scale-up; it solves the problems of low yield, long reaction time, and the need for cumbersome column chromatography purification of products in traditional acid / base buffer systems.

[0021] Specifically, this application includes two types of products. For L-phenylalanine template compounds, a reaction with 2,5-dimethoxytetrahydrofuran (DMTHF) is designed to directly yield pyrrole derivatives in high yield using water as a green solvent. Furthermore, it also includes the reaction of L-phenylalanine with 1,4-butanedialdehyde, an easily synthesized equivalent of DMTHF, as a starting material, achieving near-complete quantitative conversion to obtain the corresponding amino alcohol pyrrole derivatives. Both types of products are relatively easy to scale up, and crude products can be obtained with simple processing. The NMR spectra show extremely high purity, thus avoiding cumbersome column chromatography. Currently, the substrate expansion and yield are superior to traditional two-phase reflux and exogenous acid catalytic systems.

[0022] The crude product obtained after centrifugation is the final product of this invention. It is directly sent for NMR analysis and the purity is mostly good, and the starting material is close to quantitative complete conversion. Attached Figure Description

[0023] Figure 1 It is a protected product of L-phenylalanine pyrrole. 13 C10 NMR coarse spectrum comparison diagram;

[0024] Figures 2-3 It is the spectral data of representative analogs analyzed by nuclear magnetic resonance;

[0025] Figure 4 This is a diagram illustrating the process of obtaining a representative analogue reaction. Detailed Implementation

[0026] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0027] Example 1:

[0028] Clauson-Kaas type pyrrole cyclization reaction process (DMTHF)

[0029] This embodiment provides a green preparation method for compounds containing a chiral pyrrole skeleton, the method comprising the following steps:

[0030] Take a 5 ml capped reaction flask, add a magnetic stir bar, dissolve L-phenylalanine (16.5 mg, 0.1 mol, 1.0 equiv.) in ultrapure water (300 μL, about 20 times the volume) to obtain the template substrate, and put it into the reaction flask. Add 2,5-dimethoxytetrahydrofuran (DMTHF, 13.9 mg, 13.0 μL, 1.05 equiv.) dropwise slowly using a pipette. Generally, nitrogen protection is not required. After sealing, heat to 90 °C. The reaction progress is monitored by TLC. The reaction is almost completely converted to the target product in about 30 minutes. After the reaction (0.1 mmol scale) is completed, the product is an oily precipitate, which is purified. Specifically, the product is cooled to room temperature, then centrifuged at 8000 r / min for 5 min. The centrifuged product is dissolved in ethyl acetate or chloroform and washed with water. Then, the organic phase is dried with anhydrous sodium sulfate, and the solvent is removed by rotary evaporation to obtain the crude pyrrole protected product, which is the finished pyrrole derivative.

[0031] Example 2:

[0032] Paal-Knorr type pyrrole cyclization reaction process (1,4-butanedialdehyde)

[0033] This embodiment provides a green preparation method for compounds containing a chiral pyrrole skeleton, the method comprising the following steps:

[0034] (1) Preparation of 1,4-butanedialdehyde aqueous solution: 2,5-dimethoxytetrahydrofuran (DMTHF, 1.0 g, 37.8 mmol) was dissolved in ultrapure water (2.5 mL), and 10 wt% Amberlyst-732 resin was added. The mixture was heated to 70 °C, and the methanol produced was evaporated in an open container. After 3.5-4.5 hours, the mixture was cooled to room temperature and then filtered to remove the resin, thus obtaining 1,4-butanedialdehyde aqueous solution for later use. The pH of the 1,4-butanedialdehyde aqueous solution was approximately 7.

[0035] (2) Preparation of pyrrole derivatives: Take a 5 ml capped reaction flask, put in a magnetic stir bar, dissolve L-phenylalanine (13.7 mg, 0.1 mol, 1.0 equiv.) in ultrapure water (300 μL, about 20 times the volume) to obtain the template substrate, put it into the reaction flask, and slowly add 1,4-butanedialdehyde (0.11 mol, 1.1 equiv.) dropwise using a pipette. Generally, nitrogen protection is not required. After sealing, heat to 100 °C. The reaction progress is monitored by TLC. The reaction is almost completely converted into the target product in about 4 hours. After the reaction (0.1 mmol scale) is completed, the product is an oily precipitate. Purification is carried out by cooling the product to room temperature, centrifuging at 8000 r / min for 5 min, dissolving the centrifuged product with ethyl acetate or chloroform, washing with water, drying the organic phase with anhydrous sodium sulfate, and removing the solvent with a rotary evaporator to obtain the crude pyrrole protected product, which is the finished pyrrole derivative.

[0036] I. Based on Examples 1-2, the applicant compared the reaction conditions, including a control group with added citric acid catalysis, wherein the citric acid catalysis is the addition of the required amount of catalyst before the reactants are stirred.

[0037] Coarse weight: The weight of the organic phase after drying with anhydrous sodium sulfate, filtration, vacuum distillation or natural air drying. Some samples may contain trace amounts of residual moisture and other impurities.

[0038] Crude yield: The crude yield is calculated as follows: 100% × actual crude product weight obtained from experiments / theoretically calculated pure product weight.

[0039] Table 1 summarizes the crude product weight and yield under different reaction conditions:

[0040] Table 1

[0041]

[0042]

[0043] As shown in Table 1, the pyrrole derivatives obtained by the method of this application are mostly of good purity, the starting materials are close to quantitative complete conversion, and the reaction conditions are mild with pure aqueous phase as the medium, the chiral center configuration is maintained, avoiding cumbersome column chromatography, and the yield is better than the traditional two-phase reflux and exogenous acid (such as citric acid) catalytic system.

[0044] like Figure 1As shown, according to the crude 13C NMR spectrum, the protected product of L-phenylalanine pyrrole only requires simple centrifugation purification. The reaction temperature was set at 90℃, and CA = citric acid. The reaction times were as follows: 0.75% CA, 1 h (Entry 1); 0.75% CA, 30 min (Entry 2); 0.75% CA, 15 min (Entry 3); 0.3% CA, 30 min (Entry 4); 0.1% CA, 30 min (Entry 5); 0.05% CA, 30 min (Entry 6); 0.01% CA, 30 min (Entry 7); 0% CA, 30 min (Entry 8); 0% CA, 15 min (Entry 9). Figure 1 It can be seen that, without an external catalyst, the reaction can be completed in 30 minutes with a starting material of 0.1 mmol. The actual yield is not significantly different from that of acid-catalyzed reactions, and the addition of acidic reagents usually has the side effect of affecting the chiral centers. At the same time, when scaled up to 24.2 mmol and heated for about 1 hour, the actual crude yield did not decrease significantly, which fully demonstrates that this scheme is suitable for industrial production applications (data are shown in Table 1 above).

[0045] Based on actual reactions, this application proposes a novel mechanism similar to the N-glycosylation of natural carbohydrates, preliminarily hypothesized to involve a self-driven catalytic pathway. The reaction principle is as follows:

[0046] Water and the weak free H+ of amino acids themselves + Under the combined effect of these two factors, the initial reaction energy barrier is significantly reduced to 9.4 kcal / mol, thereby promoting the nucleophilic attack of the N-containing fragment on 2,5-dimethoxytetrahydrofuran (DMTHF), accompanied by the elimination of methanol (partial hydrolysis of the acetal). Subsequently, H- migration yields N,O-acetal, and with the assistance of the ortho-carboxyl group, the furan unit undergoes hydrolysis and ring-opening to give an imine salt. The subsequent 1,3-H- migration generates a more stable enamine, which then undergoes further hydrolysis to remove methanol, followed by intramolecular cyclization to give a hemiacetal. Dehydration and aromatization yield the pyrrole-protected final product.

[0047] The reaction process is as follows:

[0048]

[0049] Chemical structures and related spectroscopic data of two representative compounds and two analogs of this application:

[0050] (1)(S)3-Phenylacetic-2-(1H-pyrrolo-1-yl)propionic acid

[0051]

[0052] 1H NMR (500MHz, CDCl3)δ H 7.25-7.21 (m, 3H), 7.02 (dd, J=7.6, 1.9Hz, 2H), 6.70 (t, J=2.1Hz, 2H), 6.16 (t, J=2.1Hz, 2H ), 4.78 (dd, J=9.3, 5.8Hz, 1H), 3.45 (dd, J=14.0, 5.8Hz, 1H), 3.29 (dd, J=14.0, 9.4Hz, 1H).

[0053] 13 C NMR (126MHz, CDCl3)δ C 175.21, 136.27, 128.92, 128.73, 127.25, 120.36, 109.00, 63.53, 39.15.

[0054] The above data are consistent with the standard spectra of compounds in the literature Angew. Chem. Int. Ed. 2015, 54, 11516-11520; Org. Lett. 2019, 21, 8957-8961; Adv. Synth. Catal. 2020, 362, 424-429.

[0055] (2)(S)3-Phenylacet-2-(1H-pyrrolo-1-yl)1-propanol

[0056]

[0057] 1 H NMR (500MHz, CDCl3)δ H 7.27-7.19 (m, 3H), 7.04 (d, J=7.0Hz, 2H), 6.70 (t, J=2.2Hz, 2H), 6.17 (t, J=2.1Hz, 2 H), 4.19 (quintet, J=6.2Hz, 1H), 3.81 (d, J=5.9Hz, 2H), 3.06 (dd, J=7.3, 3.6Hz, 2H).

[0058] 13 C NMR (126MHz, CDCl3)δ C 137.72, 128.98, 128.64, 126.79, 119.36, 108.54, 65.41, 63.64, 38.71.

[0059] The above data are consistent with the standard spectra of the compounds in the literature Chem. Eur. J. 2020, 26, 8951-8957.

[0060] (3)Methyl (S)3-hydroxy-2-(1H-pyrrolo-1-yl)propionate

[0061]

[0062] 1 H NMR (500MHz, CDCl3) δ6.77 (t, J=2.1Hz, 2H), 6.22 (t, J=2.2Hz, 2H), 4.80-4.74 ( m, 1H), 4.16 (dd, J=11.6, 5.8Hz, 1H), 4.07 (dd, J=11.7, 6.8Hz, 1H), 3.77 (s, 3H).

[0063] 13 C NMR (126MHz, CDCl3) δ169.91, 120.59, 109.37, 63.55, 63.25, 52.95.

[0064] The above data are consistent with the standard spectra of the compounds in the literature Tetrahedron Lett. 2006, 47, 799-801.

[0065] The reaction processes of the two representative compounds mentioned above are as follows: Figure 4 As shown.

[0066] (4)(S)3-hydroxy-2-(1H-pyrrolo-1-yl)propionic acid

[0067]

[0068] 1 H NMR (500MHz, D2O) δ6.87 (t, J=2.1Hz, 2H), 6.22 (t, J=2.1Hz, 2H), 4.70 (dd, J=9.0, 4.5Hz, 1H), 4.17-4.04 (m, 1H), 1.93 (d, J=2.1Hz, 1H).

[0069] 13 C NMR (126MHz, D2O) δ 176.13, 120.93, 107.75, 66.03, 62.57 (trace residual solvent).

[0070] The above data can be directly compared and analyzed with methyl ester derivatives, as the only difference lies in the methylation fragment.

[0071] Figures 1-3 Spectral data for NMR analysis of compounds, from Figures 1-3 As can be seen, the spectral data is consistent with known pyrrole derivatives, indicating that the scheme in this application has universality.

[0072] The scope of protection of this invention includes primary amines (amino acids / alcohols or their structural analogs or derivatives) containing chiral fragments, γ-dicarbonyl compounds or their equivalents (aldehydes or substituted ketones) applicable to the above-mentioned unique reaction principle and green solvent system.

[0073] The above embodiments are merely examples of several implementations of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the present invention.

Claims

1. A method for preparing a compound containing a chiral pyrrole skeleton, characterized in that, The method includes the following steps: Take a reaction flask, place a magnetic stir bar inside, dissolve L-phenylalanine in pure water to obtain the template substrate, place it in the reaction flask, and slowly add 1,4-butanedialdehyde aqueous solution with pH 7.0 dropwise using a pipette. Seal the flask and heat to 90-100℃, reacting for 0.5-4 hours. After the reaction, cool the product to room temperature, then centrifuge at 8000 r / min for 4-6 min. Dissolve the centrifuged product in a solvent, wash with water, dry the organic phase with anhydrous sodium sulfate, and remove the solvent using a rotary evaporator to obtain the compound containing the chiral pyrrole skeleton. This compound is: ( S 3-Phenyl-2-(1H-pyrrolo-1-yl)1-propanol.

2. The method as described in claim 1, characterized in that, The reaction flask is a capped reaction flask with a volume of 5 ml.

3. The method as described in claim 1, characterized in that, The solvent is ethyl acetate or chloroform.

4. The method as described in claim 1, characterized in that, The 1,4-butanedialdehyde aqueous solution is obtained by the following method: 2,5-dimethoxytetrahydrofuran is dissolved in pure water, and 10 wt% Amberlyst-732 resin is added as a catalyst. The mixture is heated to 70°C, and the methanol produced is evaporated in an open container. After 3.5-4.5 hours, the mixture is cooled to room temperature, and then the resin is removed by filtration to obtain the 1,4-butanedialdehyde aqueous solution for later use.

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