Chiral tetrahydroquinoline compound and preparation method thereof
Through the asymmetric transfer hydrogenation reaction of chiral phosphoric acid catalyst and Hans esters, the problem of single structure and poor diversity in the synthesis of existing chiral tetrahydroquinoline compounds is solved, and multichiral, continuous chiral or ring is achieved High-efficiency synthesis of novel chiral tetrahydroquinoline compounds with exochia.
Patent Information
- Application Number
- CN202411543537.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-31
- Publication Date
- 2025-02-07
AI Technical Summary
The existing chiral tetrahydroquinoline compound synthesis strategies have the problem of single product structure and poor diversity, especially in the construction of tetrahydroquinoline structures containing multichiral, continuous chiral or extracyclic chirality.
Asymmetric transfer hydrogenation of 2-substituted quinoline substrates containing chiral substituents by using chiral phosphoric acid catalysts and Hans esters. Through dynamic kinetic resolution, a new type containing continuous chiral centers in and out of the ring is obtained. Chiral tetrahydroquinoline compounds.
The synthesis of new chiral tetrahydroquinoline compounds with excellent enantioselectivity and diastereo-selectivity has been achieved, with a significant improvement in structural diversity, simple operation, and suitable for green chemistry requirements.
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Figure CN119390646A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of pharmaceutical synthesis, and in particular to a chiral tetrahydroquinoline compound and a preparation method thereof. Background Art
[0002] Chiral tetrahydroquinoline is a type of cyclic skeleton with unique structural characteristics. It exists in many natural products with biological activity. At the same time, as a core pharmacophore, it has shown great application potential in the field of drug development. Therefore, the synthesis research of new chiral tetrahydroquinoline compounds may not only reproduce the effects of natural tetrahydroquinoline in biological activity, but also achieve better performance in terms of efficacy and stability. This research direction provides an important material basis for the discovery of new drug molecules, and may promote the development of more efficient and stable candidate drugs.
[0003] At present, there are many methods for preparing chiral tetrahydroquinoline compounds, among which the asymmetric reduction of N-heterocyclic aromatic hydrocarbons has become an important synthetic route due to its simple operation and strong practicality. Figure 1 As shown in , some studies have used iridium to catalyze the highly enantioselective asymmetric hydrogenation of quinoline, using a chiral bisphosphine ligand MeO-Bi Phep and [Ir(COD)Cl]2 to generate an in situ complex as a catalyst, assisted by iodine to activate the catalyst and generate hydroiodic acid to further activate the substrate. However, the asymmetric hydrogenation of heteroaromatic hydrocarbons is usually carried out under high pressure conditions, requiring the use of a high-pressure reactor and hydrogen, which is relatively inconvenient and potentially dangerous. Therefore, researchers have developed a metal-mediated transfer hydrogenation method to replace the direct hydrogenation reaction. Figure 2 As shown, studies have reported the use of metal Rh-catalyzed asymmetric transfer hydrogenation of quinoline to prepare 2-substituted chiral tetrahydroquinoline compounds, with remarkable results, among which the enantiomeric excess value can reach as high as 98%.
[0004] Although the above metal-mediated asymmetric hydrogenation reactions have made great progress, the reserves of these precious metals are limited and non-renewable on Earth. Therefore, researchers have begun to focus on chiral phosphoric acid catalysis strategies under mild conditions to reduce dependence on metal catalysts. Figure 3 As shown, existing studies have used chiral binaphthyl phosphate as a catalyst and hans ester as a hydrogen source to achieve an asymmetric hydrogen transfer reaction of 2-substituted quinolines, with the product enantioselectivity reaching up to 99%, broadening the scope of application of the substrate.
[0005] Although the emergence of chiral phosphoric acid catalysis has reduced the use of metals, its products are usually tetrahydroquinoline compounds containing only one chiral center. Among the currently reported chiral tetrahydroquinoline synthesis strategies, the focus is mainly on the construction of structures containing a single chiral center within the ring. The substituent types have great limitations, and the chemical space is restricted, which is not conducive to the exploration of new biological activities and also poses a major obstacle to the discovery of new drugs.
[0006] In summary, the importance of chiral tetrahydroquinoline compounds in drug development is increasing, but their current synthesis strategies face bottlenecks such as single product structure and poor diversity. In particular, there are very few tetrahydroquinoline structures containing multiple chirality, continuous chirality or exocyclic chirality, and breakthroughs are still needed. Summary of the invention
[0007] The invention adopts chiral phosphoric acid as a catalyst and Hans ester as a reducing agent to carry out asymmetric transfer hydrogenation on a 2-substituted quinoline substrate containing a chiral substituent, thereby providing a tetrahydroquinoline compound containing endo-ring and exo-ring continuous chirality and a preparation method thereof.
[0008] Specifically, the present invention provides the following technical solutions:
[0009] In a first aspect of the present invention, a chiral tetrahydroquinoline compound is provided, wherein the structure of the chiral tetrahydroquinoline compound is as follows: Figure 4 As shown; wherein R is any one of a substituted or unsubstituted acylamino group and a substituted or unsubstituted acyloxy group; R 1 is any one of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said R 1 Located at the ortho, meta or para position of the benzene ring; R 2 It is any one of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted arylalkyl; * represents a chiral center on a carbon atom.
[0010] In some embodiments, R is any one of acetylamino, acetoxy, and toluoyloxy.
[0011] In some embodiments, the R 1 It is any one of hydrogen, bromo, chloro, fluoro, methyl, methoxy, phenyl, styryl and thienyl.
[0012] In some embodiments, the R 2It is any one of methyl, ethyl, isopropyl, butyl, allyl, phenyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, naphthyl, benzofuranyl, benzodihydrofuranyl, biphenyl, p-dimethylaminophenyl, p-trifluoromethylphenyl, thiothienyl, N-methyl-substituted quinolyl, benzyl or substituted benzyl.
[0013] In a second aspect of the present invention, a method for preparing a chiral tetrahydroquinoline compound is provided, comprising: mixing a substrate, a chiral phosphoric acid catalyst, a Hans ester and a solvent for reaction, and preparing the chiral tetrahydroquinoline compound by post-treatment; the chiral phosphoric acid catalyst is 0.1 to 10 mol% of the substrate; the Hans ester is 1.5 to 3.5 equiv of the substrate; the structure of the substrate is as follows Figure 5 As shown; wherein R is any one of a substituted or unsubstituted acylamino group and a substituted or unsubstituted acyloxy group; R 1 is any one of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said R 1 Located at the ortho, meta or para position of the benzene ring; R 2 It is any one of a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted arylalkyl group.
[0014] Preferably, the chiral phosphoric acid catalyst is Figure 6 Any one of the structural formulas shown.
[0015] Preferably, the structure of the hansester is Figure 7 As shown, R 3 It is a substituted or unsubstituted C1~C4 alkyl group.
[0016] In some embodiments, the R 3 It is ethyl or tert-butyl.
[0017] In some embodiments, the solvent includes any one of chlorobenzene, ethyl acetate, and 1,4-dioxane.
[0018] In some embodiments, the method for preparing the chiral tetrahydroquinoline compound further comprises adding to the reaction system Molecular sieves, Molecular sieves, Molecular sieves or magnesium sulfate are mixed.
[0019] The beneficial effects of the present invention are:
[0020] (1) The present invention uses a chiral phosphoric acid catalyst and Hans ester to carry out asymmetric transfer hydrogenation on a 2-substituted quinoline substrate containing a chiral substituent, and obtains a series of novel chiral tetrahydroquinoline compounds containing continuous chiral centers inside and outside the ring by a dynamic kinetic resolution method. The product has a novel structure and has not been reported before, and the enantioselectivity and diastereoselectivity are well controlled.
[0021] (2) The chiral phosphoric acid catalyst used in the present invention is commercially available, and the 2-substituted quinoline is readily available and has good universal applicability, thus realizing a new synthetic strategy based on readily available raw materials.
[0022] (3) The preparation method provided by the present invention can efficiently synthesize novel chiral tetrahydroquinoline compounds, is easy to operate and can obtain the target product in a high yield, and can also maintain a good conversion rate and excellent selectivity under large-scale reaction conditions.
[0023] (4) The present invention adopts Hans ester as a hydrogen source, avoiding the use of hydrogen, thereby achieving mild reaction conditions and a safe operation process. In addition, the method has good environmental friendliness and meets the requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 is the reaction formula of the iridium-catalyzed asymmetric hydrogenation reaction of quinoline in the prior art;
[0025] Figure 2 is the reaction formula of the rhodium-catalyzed asymmetric hydrogenation reaction of quinoline in the prior art;
[0026] Figure 3 The reaction formula is a reaction formula of asymmetric hydrogen transfer reaction of 2-substituted quinoline catalyzed by chiral binaphthylphosphonic acid and using hensyl ester as hydrogen source in the prior art;
[0027] Figure 4 It is the general structural formula of a novel chiral tetrahydroquinoline compound;
[0028] Figure 5 is the general structural formula of a 2-substituted quinoline substrate containing a chiral substituent;
[0029] Figure 6 is the structural formula of a chiral phosphoric acid catalyst in one embodiment;
[0030] Figure 7 is the general structural formula of Hans ester;
[0031] Figure 8 This is the synthesis reaction formula of novel chiral tetrahydroquinoline compounds;
[0032] Fig. 9 is a synthetic reaction formula of a novel chiral tetrahydroquinoline compound in an embodiment;
[0033] Fig.10 is a synthetic reaction formula of a novel chiral tetrahydroquinoline compound in an embodiment;
[0034] Fig.11 is the structural formula of the novel chiral tetrahydroquinoline compounds 2a to 2z in an embodiment;
[0035] Fig.12 is the structural formula of novel chiral tetrahydroquinoline compounds 4a to 4ab in an embodiment;
[0036] Fig.13 1 is a single crystal structure of a novel chiral tetrahydroquinoline compound 2a in an embodiment. DETAILED DESCRIPTION
[0037] The technical solution of this patent will be further described in detail below in conjunction with specific implementation methods. It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by ordinary technicians in the technical field to which this application belongs.
[0038] like Figure 8 As shown, the present invention uses chiral phosphoric acid catalyst CPA and Hans ester HE to carry out asymmetric transfer hydrogenation on a 2-substituted quinoline substrate containing a chiral substituent, and obtains a series of novel chiral tetrahydroquinoline compounds containing continuous chiral centers inside and outside the ring through a dynamic kinetic resolution method.
[0039] Wherein, R is any one of a substituted or unsubstituted acylamino group and a substituted or unsubstituted acyloxy group; R 1 is any one of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said R 1 Located at the ortho, meta or para position of the benzene ring; R 2 is any one of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl; * represents a chiral center on a carbon atom; R 3 It is a substituted or unsubstituted C1~C4 alkyl group.
[0040] Example 1
[0041] like Fig. 9As shown, the substrate 1 is subjected to asymmetric transfer hydrogenation using chiral phosphoric acid catalyst CPA9 and Hans ester HE-1 to obtain a series of chiral tetrahydroquinoline compounds 2 containing continuous chiral centers inside and outside the ring. The specific operation steps are as follows:
[0042] (1) Under argon conditions, add substrate 1, chiral phosphoric acid catalyst CPA9, HE-1 and The reaction was carried out by stirring 1.0 mL of chlorobenzene as solvent at room temperature for 48 h. The mass of substrate 1 was 127.6 mg (0.1 mmol), CPA9 was 4.8 mg (5 mol%, 0.005 mmol), and HE-1 was 63.3 mg (2.5 equiv, 0.25 mmol). is 50mg.
[0043] (2) After the reaction is completed, the reaction system is filtered and a saturated sodium carbonate solution is added to neutralize it. Thereafter, the reaction system is extracted with dichloromethane, and the resulting organic phase is washed with a saturated sodium chloride solution to further remove water-soluble impurities. Next, anhydrous sodium sulfate is added to the organic phase for drying, and the desiccant is removed by filtration. Thereafter, the filtrate is rotary evaporated to remove the solvent to obtain a crude product, which is then purified by column chromatography to obtain the target compounds 2a to 2u, 2z.
[0044] It should be understood that the preparation methods of the following Examples 2 to 4 are similar to those of Example 1, except that the chemicals involved in step (1) and their amounts are different, and accordingly, the target compound obtained in step (2) is also different. Therefore, the following mainly introduces the differences in step (1).
[0045] Example 2
[0046] The difference between this embodiment and embodiment 1 is that: step (1) uses CPA6 as a chiral phosphoric acid catalyst, and its addition amount is 9.2 mg (10 mol%, 0.01 mmol); accordingly, after post-treatment, the target compounds obtained are 2v to 2y.
[0047] Example 3
[0048] like Fig.10 As shown, substrate 3 was subjected to asymmetric transfer hydrogenation using chiral phosphoric acid catalyst CPA10 and Hans ester HE-2 to obtain a series of chiral tetrahydroquinoline compounds 4 containing continuous chiral centers within and outside the ring.
[0049] Specifically, substrate 3, chiral phosphoric acid catalyst CPA10 and HE-2 were added to a Schlenk tube with a capacity of 10 mL in sequence, and ethyl acetate with a volume of 2.0 mL was used as a solvent, and the reaction was stirred at room temperature for 48 hours. Among them, the mass of substrate 3 was 55.4 mg (0.2 mmol), CPA10 was 7.6 mg (5 mol%, 0.01 mmol), and HE-2 was 154.7 mg (2.5 equiv, 0.5 mmol). After post-treatment, the target compounds obtained were 4a to 4w. Among them, when preparing compounds 4b and 4q, the stirring environment temperature was 40°C, that is, the temperature was raised to 40°C for reaction.
[0050] Example 4
[0051] Under argon conditions, substrate 3, chiral phosphoric acid catalyst CPA4 and HE-1 were added to a 10 mL Schlenk tube in sequence, and 2.0 mL of ultra-dry 1,4-dioxane was used as a solvent. The reaction was stirred at room temperature for 48 hours. Among them, the mass of substrate 3 was 63.5 mg (0.2 mmol), CPA4 was 7.5 mg (5 mol%, 0.01 mmol), and HE-1 was 126.6 mg (2.5 equiv, 0.5 mmol). After post-treatment, the target compounds obtained were 4x to 4ab. Among them, when preparing compounds 4z and 4aa, the stirring environment temperature was 40°C, that is, the temperature was raised to 40°C for reaction; when preparing compound 4ab, the addition amount of substrate 3 was 0.1 mmol, and the addition ratio of other substances remained unchanged.
[0052] In Examples 1 to 4, R in the general structural formula of substrates 1, 3 and chiral tetrahydroquinoline compounds 2, 4 is 1 is any one of hydrogen, bromo, chloro, fluoro, methyl, methoxy, phenyl, styryl, and thienyl; R 2 It is any one of methyl, ethyl, isopropyl, butyl, allyl, phenyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, naphthyl, benzofuranyl, benzodihydrofuranyl, biphenyl, p-dimethylaminophenyl, p-trifluoromethylphenyl, thiothienyl, N-methyl substituted quinolyl, benzyl or substituted benzyl; R in the general structural formula of substrate 3 and chiral tetrahydroquinoline compound 4 is acetoxy or toluoyloxy.
[0053] result
[0054] Fig.11 The structural formulas of compounds 2a to 2z prepared in Example 1 or Example 2 are shown; Fig.12 The structural formulas of compounds 4a to 4ab prepared in Example 3 or Example 4 are shown.
[0055] Table 1 series shows the characterization results of compounds 2a to 2z, and Table 2 series shows the characterization results of compounds 4a to 4ab. Table 1-1 includes and Table 2-1 includes morphology, mass, yield, diastereomeric ratio (dr), enantiomeric excess (ee) and specific rotation ([α] 25D ) results; Table 1-2 and Table 2-2 include 1 H NMR spectroscopy and 13 C NMR spectrum results; Tables 1-3 and 2-3 include high-resolution mass spectrometry and high-performance liquid chromatography results.
[0056] Table 1-1 The form, mass, yield, isomer ratio, enantiomeric excess and specific rotation results of compounds 2a to 2z
[0057]
[0058]
[0059] Table 1-2 Compounds 2a to 2z 1 H NMR spectroscopy, 13 C NMR spectrum results
[0060]
[0061]
[0062]
[0063]
[0064]
[0065] Table 1-3 High-resolution mass spectrometry and high-performance liquid chromatography results of compounds 2a to 2z
[0066]
[0067]
[0068]
[0069] Table 2-1 The form, mass, yield, isomer ratio, enantiomeric excess and specific rotation results of compounds 4a to 4ab
[0070]
[0071]
[0072]
[0073] Table 2-2 4a to 4ab 1 H NMR spectroscopy, 13 C NMR spectrum results
[0074]
[0075]
[0076]
[0077]
[0078]
[0079]
[0080] Table 2-3 High-resolution mass spectrometry and high-performance liquid chromatography results of compounds 4a to 4ab
[0081]
[0082]
[0083]
[0084] Compounds 2l, 4g, 4r 19 The results of the F NMR spectrum are as follows: 2l: 19 F NMR (376MHz, CDCl3): δ-62.6; 4g: 19 F NMR (376MHz, CDCl3): δ-113.17; 4r: 19 F NMR (376MHz, CDCl3): δ-127.72.
[0085] The compound 2a obtained in Example 1 was identified by nuclear magnetic resonance, X-ray single crystal diffraction and other instruments and the results are as follows: Fig.13 And as shown in Table 3.
[0086] Table 3 Main parameters of compound 2a
[0087]
[0088]
[0089] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.
Claims
1. A chiral tetrahydroquinoline compound, characterized in that: The structure of the chiral tetrahydroquinoline compound is shown in formula (1): Wherein, R is any one of a substituted or unsubstituted acylamino group and a substituted or unsubstituted acyloxy group; R 1 is any one of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said R 1 Located at the ortho, meta or para position of the benzene ring; R 2 is any one of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted arylalkyl; * indicates a chiral center on a carbon atom.
2. The chiral tetrahydroquinoline compound according to claim 1, characterized in that The R is any one of acetylamino, acetoxy, and toluoyloxy.
3. The chiral tetrahydroquinoline compound according to claim 1, characterized in that The R 1 It is any one of hydrogen, bromo, chloro, fluoro, methyl, methoxy, phenyl, styryl and thienyl.
4. The chiral tetrahydroquinoline compound according to any one of claims 1 to 3, characterized in that The R 2 It is any one of methyl, ethyl, isopropyl, butyl, allyl, phenyl, tolyl, methoxyphenyl, chlorophenyl, fluorophenyl, naphthyl, benzofuranyl, benzodihydrofuranyl, biphenyl, p-dimethylaminophenyl, p-trifluoromethylphenyl, thiothienyl, N-methyl-substituted quinolyl, benzyl or substituted benzyl.
5. A method for preparing a chiral tetrahydroquinoline compound, characterized in that: include: Mixing a substrate, a chiral phosphoric acid catalyst, a Hans ester and a solvent for reaction, and preparing the chiral tetrahydroquinoline compound through post-treatment; The chiral phosphoric acid catalyst is 0.1-10 mol% of the substrate; the Hans ester is 1.5-3.5 equiv of the substrate; The structure of the substrate is shown in formula (2): Wherein, R is any one of a substituted or unsubstituted acylamino group and a substituted or unsubstituted acyloxy group; R 1 is any one of hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; said R 1 Located at the ortho, meta or para position of the benzene ring; R 2 It is any one of a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted arylalkyl group.
6. The method for preparing a chiral tetrahydroquinoline compound according to claim 5, characterized in that: The chiral phosphoric acid catalyst is any one of the following structural formulas:
7. The method for preparing a chiral tetrahydroquinoline compound according to claim 5, characterized in that: The structure of the hans ester is shown in formula (3): Among them, R 3 It is a substituted or unsubstituted C1~C4 alkyl group.
8. The method for preparing a chiral tetrahydroquinoline compound according to claim 7, characterized in that: The R 3 It is ethyl or tert-butyl.
9. The method for preparing a chiral tetrahydroquinoline compound according to any one of claims 5 to 8, characterized in that: The solvent includes any one of chlorobenzene, ethyl acetate and 1,4-dioxane.
10. The method for preparing a chiral tetrahydroquinoline compound according to claim 9, characterized in that: It also includes adding to the reaction system Molecular sieves, Molecular sieves, Molecular sieves or magnesium sulfate are mixed.