A nitrogen-centered chiral troger base derivative, its preparation method and application

Abstract

The application belongs to the technical field of organic chemical synthesis, and particularly relates to a nitrogen center chiral base derivative, a preparation method and application thereof. The preparation method of the nitrogen center chiral base derivative provided by the application can effectively synthesize a base with only a nitrogen chiral center by using a tetrahydrodibenzo-diazocine compound as a raw material and through chiral phosphoric acid catalyzed amination reaction. Moreover, the synthesis method provided by the application has the advantages of high efficiency, simple steps and strong enantioselectivity, is suitable for industrialized production of chiral bases and derivatives thereof, and provides a new approach for research and application of chiral compounds. Meanwhile, the base derivative prepared by the application is a base molecule with a nitrogen center chirality, and has wide application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, material science, asymmetric catalysis and drug development.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a nitrogen-centered chiral... Alkali derivatives, their preparation methods, and applications. Background Technology

[0002] In the field of chiral chemistry, chiral nitrogen compounds have broad application prospects in molecular recognition, drug development and asymmetric catalysis due to their unique structural characteristics. Bases (TB), as classic chiral nitrogen compounds, were first discovered by Julius... Obtained accidentally in 1887 through the condensation reaction of p-toluidine and formaldehyde, TB has a rigid Λ-shaped molecule with C2 symmetry. Since its discovery, TB has become an important model compound in the study of "chiral nitrogen" and has been widely used in stereochemistry-related research.

[0003] Although the synthesis of TB has a long history, obtaining optically pure TB remains a challenge. The main existing TB synthesis method involves the resolution of racemic TB using high-performance liquid chromatography (HPLC) with a chiral stationary phase. However, this method suffers from low efficiency and high cost, making it difficult to meet the needs of practical applications. Therefore, developing a new, direct, and convenient catalytic asymmetric synthesis method for TB is of great significance for promoting the further expansion of TB applications. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the primary objective of this invention is to provide a nitrogen-centered chiral... A base derivative, which is a chiral compound with a nitrogen center. Base molecules have broad application prospects in fields such as molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis, and drug development.

[0005] A second objective of the present invention is to provide the above-mentioned nitrogen-centered chirality. The preparation method of the alkali derivative is simple and can produce alkali derivatives with a wide range of rigid Λ-shaped structures. The base product can be synthesized with high enantioselectivity to synthesize structurally challenging chiral bibasic products. Alkali and Tri Alkali.

[0006] A third objective of the present invention is to provide the above-mentioned nitrogen-centered chirality. Applications of alkali derivatives.

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

[0008] A nitrogen-centered chiral Base derivatives, selected from compounds I-1 to I-18 with the following structures:

[0009]

[0010]

[0011]

[0012] The nitrogen-centered chirality provided by this invention The base derivative is a chiral compound with a nitrogen center. Base molecules have broad application prospects in fields such as molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis, and drug development.

[0013] The above-mentioned nitrogen-center chirality A method for preparing a base derivative includes the following steps: reacting compound 1, compound 2, an additive, and a chiral phosphoric acid catalyst in an organic solvent, followed by purification to obtain a nitrogen-centered chiral base. Alkali derivatives;

[0014] Compound 1 is selected from

[0015] One of them;

[0016] The structure of compound 2 is shown in Formula II:

[0017]

[0018] In Equation II, R 1 Selected from p-bromoyl, p-alkynyl, p-formyl, p-cholesterol ester, p-geraniol ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, One of 3,5-dicarboxyloyl and 3,5-bis(p-formylphenyl).

[0019] The nitrogen-centered chirality provided by this invention The preparation method of base derivatives, for the first time, uses tetrahydrodibenzodiazepines and aromatic aldehydes as raw materials, and successfully applies them to chiral applications. Efficient Synthesis of Bases (TB) and Their Derivatives. Furthermore, this invention enables the efficient synthesis of TB with only nitrogen chiral centers via a chiral phosphoric acid-catalyzed amination reaction. The synthetic method provided by this invention has the advantages of high efficiency, simple steps, and strong enantioselectivity, making it suitable for the industrial production of chiral TB and its derivatives, and providing a new avenue for the research and application of chiral compounds.

[0020] As a preferred solution, the chiral phosphoric acid catalyst is an R configuration chiral phosphoric acid or an S configuration chiral phosphoric acid.

[0021] As a further preferred solution, the R configuration chiral phosphoric acid has a structural formula of: The S configuration chiral phosphoric acid has a structural formula of:

[0022] As a preferred solution, the organic solvent is one or more of chloroform, methane, dichloromethane, tetrahydrofuran. As a further preferred solution, the organic solvent is chloroform.

[0023] As a preferred solution, the additive is Molecular sieve. By using the additive, a water removal effect is achieved, ensuring smooth progress of the reaction.

[0024] As a preferred solution, the molar ratio of compound 1, compound 2 and chiral phosphoric acid catalyst is (1-3.6):(1-1.2):(0.04-0.06).

[0025] As a preferred solution, for every 1-3.6 mmol of compound 1, the amount of additive used is 0.9-1.2 g.

[0026] As a preferred solution, the purification is column chromatography purification.

[0027] The above-mentioned nitrogen center chiral Base derivative is used in molecular recognition, DNA binding or asymmetric catalysis.

[0028] The above-mentioned technical solutions of the present application have the following advantages compared with the prior art:

[0029] (1) The preparation method provided by the present application uses tetrahydrodibenzo-diazocyclic compound and aromatic aldehyde as starting reaction raw materials, which are cheap and easy to obtain.

[0030] (2) The nitrogen center chiral Base prepared by the present application is easy to modify, and different products can be obtained modularly by selecting different substrates;

[0031] (3) The nitrogen center chiral Base prepared by the present application has excellent yield and good enantioselectivity;

[0032] (4) The nitrogen center chiral Base prepared by the present application has a novel structural skeleton, which is complementary to traditional Base compound type;

[0033] (5) The nitrogen center chiral alkaline, has good application value, can form chiral double alkaline or tri alkaline, high enantioselectivity, wide application prospect in fields of molecular recognition, DNA binding, supramolecular chemistry, material science, asymmetric catalysis and drug development. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 HPLC result chart of racemic compound I-1 in the embodiment 1 of the application;

[0035] Figure 2 HPLC result chart of chiral compound I-1 in the embodiment 1 of the application;

[0036] Figure 3 HPLC result chart of racemic compound I-2 in the embodiment 2 of the application;

[0037] Figure 4 HPLC result chart of chiral compound I-2 in the embodiment 2 of the application;

[0038] Figure 5 HPLC result chart of racemic compound I-3 in the embodiment 3 of the application;

[0039] Figure 6 HPLC result chart of chiral compound I-3 in the embodiment 3 of the application;

[0040] Figure 7 HPLC result chart of racemic compound I-4 in the embodiment 4 of the application;

[0041] Figure 8 HPLC result chart of chiral compound I-4 in the embodiment 4 of the application;

[0042] Figure 9 HPLC result chart of racemic compound I-5 in the embodiment 5 of the application;

[0043] Figure 10 HPLC result chart of chiral compound I-5 in the embodiment 5 of the application;

[0044] Figure 11 HPLC result chart of racemic compound I-6 in the embodiment 6 of the application;

[0045] Figure 12 HPLC result chart of chiral compound I-6 in the embodiment 6 of the application;

[0046] Figure 13 HPLC result chart of racemic compound I-7 in the embodiment 7 of the application;

[0047] Figure 14 Figure 1 shows the HPLC results of the chiral compound of Example 7. DETAILED DESCRIPTION

[0048] The present application will be further described in conjunction with specific examples so that those skilled in the art can better understand the present application and implement it. However, the examples are not intended to limit the present application. The test methods used in the following examples are conventional methods unless otherwise specified. The raw materials used in the examples are conventional materials commonly used in the art, publicly available or commercially available unless otherwise specified.

[0049] In the present application, the abbreviations of the substituents are commonly understood in the art, such as "Me" for methyl, "F" for fluorine, "Cl" for chlorine, "Br" for bromine, "MeO" for methoxy, and "Ph" for phenyl.

[0050] In the following examples, the nitrogen center chiral compound is The method for preparing the base derivative includes the following steps: reacting compound 1, compound 2, an additive and a chiral phosphoric acid catalyst in an organic solvent, and then purifying to obtain the nitrogen center chiral compound. The base derivative.

[0051] Specifically, the nitrogen center chiral compound in the following provided Examples 1-18 is The method for preparing the base derivative, and the nitrogen center chiral compound prepared thereby. The base derivatives are sequentially numbered as compounds I-1-I-18.

[0052] In the following examples, compound 1 is a tetrahydrodibenzo-diazepine compound, and the structural formula is

[0053] and are sequentially numbered as compounds 1a-1e.

[0054] Further, the compound 1 in the present application can be prepared by referring to the prior art. Specifically, in the following examples, compounds 1a-1d can be prepared by referring to the conventional preparation in the prior art [1] and [2]:

[0055] [1]. Functionalized analogues of Tro¨ger’s base: scope and limitations of a general synthetic procedure and facile, predictable method for the separation of enantiomers. doi.org / 10.1016 / j.tet.2008.04.111;

[0056] [2] Synthesis of 5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocines and a demonstration of their reactivity to afford methano strap-modified base analogues. DOI: 10.3998 / ark.5550190.0009.c17.

[0057] Compound 1e can be routinely prepared based on the existing literature [3]:

[0058] [3] Carmen Pardo, Celine Pirat, Jose Elguero. The synthesis of a linear Trger's base derived from naphthalene: 7H-15H-6,14-methanodinaphtho[2,3-b:2',3'-f][1,5]diazocine [J]. Journal of Heterocyclic Chemistry, 2009, 44(6): 1303-1307. DOI: 10.1002 / jhet.5570440611.

[0059] The following examples relate to compound 2, whose structure is shown in formula II:

[0060]

[0061] In formula II, R 1 is selected from p-bromophenyl, p-alkynyl, p-formyl, p-cholesterol ester, p-geranyl ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, One of 3,5-diformyl or 3,5-bis(p-formylphenyl). Specifically, the compounds 2 involved in the following examples are referred to as compounds 2a to 2m, all of which have the general structural formula shown in Formula II.

[0062] In the following examples, the chiral phosphoric acid catalyst is either R-configuration chiral phosphoric acid or S-configuration chiral phosphoric acid. The structural formula of R-configuration chiral phosphoric acid is: The structural formula of S-configuration chiral phosphoric acid is:

[0063] Furthermore, the racemic phosphoric acid catalyst used in the preparation of the racemic compounds in the following examples has the following structural formula:

[0064] Example 1

[0065] This embodiment provides a nitrogen-centered chiral... The base derivative (denoted as chiral compound I-1) is an enantiomeric pure nitrogen-centered chiral compound. The base derivative has the following structural formula: The preparation method of this compound is as follows:

[0066] Compound 1a (structural formula: 0.1mmol) Molecular sieve (i.e.) MS (100 mg) and R-configuration chiral phosphoric acid catalyst (0.005 mmol, 4.2 mg) were dissolved in CHCl3 (1 mL), and compound 2a (R) was added over 5 minutes. 1 =p-bromo group, 0.12 mmol), and stirred at -40 °C until the starting material was completely consumed (as detected by TLC). The solvent was removed under vacuum, and the crude product was purified by column chromatography with ethyl acetate / dichloromethane = 10 / 1 as the developing solvent to give chiral compound I-1, 38.8 mg in total, in 96% yield, as a white solid.

[0067] Furthermore, racemic compound I-1 was prepared for comparison with the chiral compound I-1 prepared above in this invention. The preparation process of racemic compound I-1 is as follows: compound 1a (structural formula is...) was prepared... 0.1 mmol) and racemic phosphoric acid catalyst (0.005 mmol, 1.75 mg) were dissolved in CHCl3 (1 mL), and compound 2a (R) was added over 5 minutes. 1 =p-bromo group, 0.12 mmol), the reaction was stirred at room temperature until the starting material was completely consumed (detected by TLC), then the solvent was removed under vacuum, and the crude product was separated by rapid column chromatography on silica gel to give racemic compound I-1.

[0068] The HPLC result chart of the racemic compound I-1 prepared in Example 1 of the present application is shown in Figure 1; the HPLC result chart of the chiral compound I-1 is shown in Figure 2. Figure 1 Figure 2 The successful preparation of the chiral compound of the present application can be seen from the HPLC result charts.

[0069] The analytical data of the chiral compound I-1 of Example 1 are as follows: the melting point M.p. is 64.5-64.7℃. The optical rotation value is +156.0 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (IJ chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 4.61 min, peak time 2 is 6.45 min, enantioselectivity is 96%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDC13) δ 7.47 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.97-6.92 (m, 2H), 6.76 (s, 1H), 6.45 (s, 1H), 5.22 (s, 1H), 4.77 (d, J = 16.5 Hz, 1H), 4.29 (d, J = 16.6 Hz, 1H), 4.08 (d, J = 17.0 Hz, 1H), 3.87 (d, J = 17.0 Hz, 1H), 2.23 (s, 3H), 2.12 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 147.4, 143.4, 137.6, 133.6, 133.3, 131.4, 129.5, 128.2, 128.1, 127.5, 127.3, 126.9, 125.4, 125.1, 121.4, 74.2, 60.7, 52.6, 20.9, 20.8. HRMS (ESI) m / z calcd for C 23 H 21 BrN2[M+H] + = 405.0961, found = 405.0958.

[0070] Example 2

[0071] This example provides a nitrogen center chiral base derivative (denoted as chiral compound I-2), which is an enantiomerically pure nitrogen center chiral base derivative, and the structural formula is: ​​​The preparation method of the compound is basically the same as that in Example 1, except that compound 1a in Example 1 is adjusted to compound 1b (the structural formula of compound 1b is ), and the remaining steps are the same as those in Example 1. The prepared product is chiral compound I-2, 47.5 mg in total, with a yield of 86% and in the form of a white solid.

[0072] Referring to the preparation method of racemic compound I-1 in Example 1, compound 1a is adjusted to compound 1b, and the remaining conditions remain unchanged, to prepare racemic compound I-2.

[0073] The HPLC result graph of racemic compound I-2 prepared in Example 2 of the present application is shown in Figure 3 ; and the HPLC result graph of chiral compound I-2 is shown in Figure 4 . It can be seen from the HPLC result graph that the chiral compound is successfully prepared.

[0074] The analytical data of chiral compound I-2 of Example 2 are as follows: the melting point M.p. is 68.4-68.8°C. The optical rotation value is +102.0 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (AD chiral column, isopropanol / n-hexane = 10 / 90, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 6.17 min, peak time 2 is 6.76 min, and the enantioselectivity is 96%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 4H), 7.45-7.23 (m, 14H), 7.21-7.17 (m, 1H), 6.86 (s, 1H), 5.29 (s, 1H), 4.88 (d, J = 16.5 Hz, 1H), 4.45 (d, J = 16.6 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 4.04 (d, J = 17.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 149.4, 145.4, 140.7, 140.6, 137.2, 137.2, 136.9, 131.5, 129.6, 128.8, 128.7, 128.6, 128.1, 127.1, 127.0, 126.9, 126.8, 126.5, 126.3, 126.1, 125.8, 125.6, 125.2, 121.6, 74.2, 60.8, 52.7. HRMS (ESI) m / z calcd for C 33 H 25 BrN2[M+H] + = 529.1274, found = 529.1254.

[0075] Example 3

[0076] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-3), which is enantiomerically pure nitrogen center chiral base derivative, the structural formula of which is: The preparation method of the compound is basically the same as that in Example 1, except that compound 1a in Example 1 is adjusted to compound 1c (the structural formula of compound 1c is ), the R configuration chiral phosphoric acid is adjusted to S configuration chiral phosphoric acid, and the remaining steps are the same as those in Example 1. The developing agent is ethyl acetate / ethyl acetate = 20 / 1, and the prepared product is chiral compound syn I-3, 36.5 mg in total, with a yield of 83%, in the form of white solid.

[0077] Referring to the preparation method of racemic compound I-1 in Example 1, compound 1a is adjusted to compound 1c, and the remaining conditions remain unchanged, to prepare racemic compound I-3.

[0078] The HPLC result graph of racemic compound I-3 prepared in Example 3 of the present application is shown in Figure 5 ; and the HPLC result graph of chiral compound syn I-3 is shown in Figure 6 From the HPLC result graph, it can be seen that the chiral compound of the present application is successfully prepared.

[0079] The analytical data of chiral compound syn I-3 of Example 3 are as follows: the melting point M.p. is 65.2-65.5°C. The optical rotation value is: -231.5 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (AD chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 5.19 min, peak time 2 is 6.19 min, and the enantioselectivity is 90%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDC13) δ 7.45-7.38 (m, J = 8.5 Hz, 4H), 6.91 (d, J = 10.7 Hz, 1H), 6.84 (d, J = 10.7 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 8.3 Hz, 1H), 5.18 (s, 1H), 4.71 (d, J = 16.4 Hz, 1H), 4.25 (d, J = 16.3 Hz, 1H), 4.03 (d, J = 16.8 Hz, 1H), 3.83 (d, J = 16.8 Hz, 1H), 2.15 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz, CDC13) δ 160.4 (d, J = 242 Hz), 160.3 (d, J = 243 Hz), 148.7 (d, J = 10 Hz), 144.7 (d, J = 10 Hz), 131.5, 129.4, 129.3, 129.2 (d, J = 6 Hz), 128.9 (d, J = 6 Hz), 123.4 (d, J = 3 Hz), 122.8 (d, J = 3 Hz), 121.6, 121.2 (d, J = 20 Hz), 121.0 (d, J = 20 Hz), 111.5 (d, J = 23 Hz), 111.3 (d, J = 23 Hz), 73.8, 60.0, 52.0, 14.2 (d, J = 3 Hz), 14.12, 14.1 (d, J = 3 Hz). 19 F NMR (376 MHz, CDC13) δ -118.37, -118.83. HRMS (ESI) m / z calcd for C 23 H 19 BrF2N2[M+H] + = 441.0773, found = 441.0773.

[0080] Example 4

[0081] The present example provides a nitrogen center chiral base derivative (denoted as chiral compound anti-configuration I-4), which is an enantiomerically pure nitrogen center chiral base derivative, and the structural formula is as follows: The preparation method of the compound is basically the same as that in Example 1, except that compound 1a in Example 1 is adjusted to compound 1d (the structural formula of compound 1d is ), the chiral phosphoric acid of R configuration is adjusted to chiral phosphoric acid of S configuration, and the remaining steps are the same as those in Example 1. The developing agent is ethyl acetate / ethyl acetate = 2 / 1, and the prepared product is chiral compound anti-configuration I-4, 5.6 mg in yield, and white solid in state.

[0082] Referring to the preparation method of racemic compound I-1 in Example 1, compound 1a is adjusted to compound 1d, and the remaining conditions are unchanged, to prepare racemic compound I-4.

[0083] The HPLC result graph of racemic compound I-4 prepared in Example 4 of the present application is shown in Figure 7 ; and the HPLC result graph of chiral compound anti-configuration I-4 is shown in Figure 8 . It can be seen from the HPLC result graph that the chiral compound of the present application is successfully prepared.

[0084] The analytical data of the chiral compound epimer I-4 of Example 4 are as follows: the melting point M.p. is 156.2-156.7°C. The optical rotation value is: -100.3 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (AD chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 7.47 min, peak time 2 is 11.90 min, and the enantioselectivity is 90%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDC13) δ 7.46-7.39 (m, 4H), 6.79-6.73 (m, 2H), 6.44 (s, 1H), 6.14 (s, 1H), 5.20 (d, J = 3.4 Hz, 1H), 4.74 (d, J = 15.9 Hz, 1H), 4.28 (d, J = 16.1 Hz, 1H), 4.00 (d, J = 16.7 Hz, 1H), 3.93-3.85 (m, 7H), 3.79 (s, 3H), 3.68 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 148.6, 148.4, 146.3, 146.0, 142.5, 138.3, 137.5, 131.3, 129.4, 121.4, 119.4, 118.9, 108.8, 108.5, 108.4, 108.3, 74.3, 59.9, 56.0, 55.7, 52.0. HRMS (ESI) m / z calcd for C 25 H 25 BrN2O4[M+H] + = 497.1071, found = 497.1071.

[0085] Example 5

[0086] This example provides a nitrogen center chiral base derivative (denoted as chiral compound epimer I-5), which is an enantiomerically pure nitrogen center chiral base derivative, and the structural formula is: The preparation method of the compound is basically the same as that of Example 1, and the difference is that the compound 1a in Example 1 is adjusted to the compound 1e (the structural formula of the compound 1e is ), the chiral phosphoric acid of the R configuration is adjusted to the chiral phosphoric acid of the S configuration, and the remaining steps are the same as those of Example 1. The developing agent is ethyl acetate / ethyl acetate = 2 / 1, and the prepared product is the chiral compound epimer I-5, which is 45.6 mg in yield, and is a white solid.

[0087] Reference to the preparation method of racemic compound I-1 in Example 1, compound 1a is adjusted to compound 1e, and the rest conditions are unchanged, to prepare racemic compound I-5.

[0088] The HPLC result chart of racemic compound I-5 prepared in Example 5 of the present application is shown in Figure 1. Figure 9 The HPLC result chart of chiral compound epimer I-5 is shown in Figure 2. Figure 10 From the HPLC result chart, it can be seen that the chiral compound of the present application is successfully prepared.

[0089] The analytical data of chiral compound epimer I-5 of Example 5 are as follows: the melting point M.p. is 72.1-72.6℃. The optical rotation value is: -105.0 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (AD chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 6.43 min, peak time 2 is 8.15 min, and the enantioselectivity is 84%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.77-7.70 (m, 3H), 7.65-7.49 (m, 4H), 7.44-7.25 (m, 7H), 7.13 (s, 1H), 5.49 (s, 1H), 5.16 (d, J = 16.5 Hz, 1H), 4.76 (d, J = 16.6 Hz, 1H), 4.51 (d, J = 17.1 Hz, 1H), 4.33 (d, J = 17.1 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 148.6, 145.1, 137.3, 133.3, 133.1, 131.5, 130.8, 130.6, 129.6, 127.9, 127.4, 127.2, 127.1, 126.8, 125.7, 125.6, 125.5, 125.1, 125.0, 124.9, 122.9, 122.4, 121.6, 74.3, 62.7, 54.4. HRMS (ESI) m / z calcd for C 29 H 21 BrN2[M+H] + = 477.0961, found = 477.0965.

[0090] Example 6

[0091] This example provides a nitrogen-centered chiral base derivative (denoted as chiral compound epimer I-6), which is an enantiomerically pure nitrogen-centered chiral base derivative, and the structural formula is: The preparation method of the compound is basically the same as that in Example 1, except that the compound 2a in Example 1 is adjusted to be compound 2b (in compound 2b, R 1 = p-alkynyl), R configuration chiral phosphoric acid is adjusted to be S configuration chiral phosphoric acid, and the remaining steps are the same as those in Example 1. The developing agent is petroleum ether / dichloromethane = 5 / 1, and the prepared product is chiral compound anti-I-6, 31.5 mg in total, with a yield of 90%, in the form of white solid.

[0092] Referring to the preparation method of racemic compound I-1 in Example 1, compound 2a is adjusted to be compound 2b, and the remaining conditions remain unchanged, to prepare racemic compound I-6.

[0093] The HPLC result graph of racemic compound I-6 prepared in Example 6 of the present application is shown in Figure 11 The HPLC result graph of chiral compound anti-I-6 is shown in Figure 12 The HPLC result graph shows that the chiral compound is successfully prepared.

[0094] The analytical data of chiral compound anti-I-6 in Example 6 are as follows: the melting point M.p. is 164.6-164.9℃. The optical rotation value is: -370.1 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (IJ-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 5.09 min, peak time 2 is 6.37 min, and the enantioselectivity is 92%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDCI3) δ 7.57-7.54 (m, 2H), 7.43-7.37 (m, 2H), 7.16-7.07 (m, 2H), 7.00-6.92 (m, 2H), 6.74 (s, 1H), 6.43 (s, 1H), 5.27 (d, J = 3.7 Hz, 1H), 4.76 (m, 1H), 4.29 (dd, J = 16.7, 3.7 Hz, 1H), 4.08 (dd, J = 17.1, 5.1 Hz, 1H), 3.87 (dd, J = 17.1, 4.5 Hz, 1H), 3.00 (d, J = 3.8 Hz, 1H), 2.21 (d, J = 3.2 Hz, 3H), 2.10 (d, J = 2.9 Hz, 3H); 13C NMR (100MHz, CDCl3) δ147.5,143.5,139.4,133.6,133.3,132.1,128.5,128.2,127.7,127.6,12 7.4,127.0,125.5,125.2,121.0,83.8,76.9,74.5,60.7,52.7,21.0,20.9; HRMS(ESI)m / zcalcd for C 25 H 22 N2[M+H] + =351.1856,found=351.1858.

[0095] Example 7

[0096] This embodiment provides a nitrogen-centered chiral... The base derivative (denoted as chiral compound transconfiguration I-7) is an enantiomeric pure nitrogen-centered chiral compound. The base derivative has the following structural formula: The preparation method of this compound is basically the same as that in Example 1, except that compound 2a in Example 1 is replaced with compound 2c (in compound 2c, R...). 1 = (p-formyl), the R-configuration chiral phosphoric acid was adjusted to the S-configuration chiral phosphoric acid, and the remaining steps were the same as in Example 1. The developing solvent was petroleum ether / ethyl acetate = 5 / 1. The product obtained was the trans-configuration I-7 of the chiral compound, with a total yield of 30.8 mg, 87%, and was a white solid.

[0097] Referring to the preparation method of racemic compound I-1 in Example 1, compound 2a was changed to compound 2c, and the other conditions remained unchanged to prepare racemic compound I-7.

[0098] The HPLC results of racemic compound I-7 prepared in Example 7 of this invention are shown in the figure below. Figure 13 As shown; the HPLC results of the chiral compound trans-configuration I-7 are shown in the figure. Figure 14 As shown in the HPLC results, the chiral compound of this invention was successfully prepared. Similar comparison results for racemic and chiral compounds were obtained in Examples 8-18 below, and will not be repeated here.

[0099] The analytical data of the chiral compound epimer I-7 of Example 7 are as follows: the melting point M.p. is 53.2-53.9°C. The optical rotation value is: -262.2 (concentration is 0.10, solvent is chloroform). The analytical result is: HPLC (IJ-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 7.53 min, peak time 2 is 23.31 min, and the enantioselectivity is 90%. The nuclear magnetic characterization result is: 1 H NMR (400 MHz, CDC13) δ 9.92 (s, 1H), 7.77 (s, 4H), 7.22-7.10 (m, 2H), 7.01-6.96 (m, 2H), 6.77 (s, 1H), 6.44 (s, 1H), 5.32 (s, 1H), 4.79 (d, J = 16.5 Hz, 1H), 4.32 (d, J = 16.5 Hz, 1H), 4.07 (d, J = 17.1 Hz, 1H), 3.90 (d, J = 17.1 Hz, 1H), 2.23 (s, 3H), 2.12 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 192.1, 147.4, 145.4, 143.3, 135.5, 133.7, 133.4, 129.7, 128.6, 128.4, 128.2, 128.0, 127.4, 127.3, 127.0, 125.5, 125.1, 74.5, 60.7, 52.7, 20.9, 20.8; HRMS (ESI) m / z calcd for C 24 H 22 N2O[M+H] + = 355.1805, found = 355.1805.

[0100] Example 8

[0101] This example provides a nitrogen center chiral base derivative (denoted as chiral compound epimer I-8), which is an enantiomerically pure nitrogen center chiral base derivative, and the structural formula is: The preparation method of the compound is basically the same as that of Example 1, and the difference is that the compound 2a in Example 1 is adjusted to the compound 2d (in the compound 2d, R 1 = cholesteryl ester group), and the R configuration chiral phosphoric acid is adjusted to the S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 100 / 1, and the prepared product is the chiral compound epimer I-8, which is 70.9 mg in yield and white solid in state.

[0102] The analytical data of chiral compound epimer I-8 are as follows: melting point M.p. is 198.3-198.6℃. Optical rotation value is: -158.1 (concentration is 0.10, solvent is chloroform); diastereoselectivity is greater than 20:1. Nuclear magnetic characterization results: 1 H NMR (400 MHz, CDC13) δ 7.95 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.04-6.90 (m, 2H), 6.75 (s, 1H), 6.42 (s, 1H), 5.37 (s, 1H), 5.30 (s, 1H), 4.90-4.70 (m, 2H), 4.31 (d, J = 16.6 Hz, 1H), 4.07 (d, J = 17.1 Hz, 1H), 3.88 (d, J = 17.1 Hz, 1H), 2.43 (d, J = 7.5 Hz, 2H), 2.22 (s, 3H), 2.11 (s, 3H), 2.06-1.78 (m, 5H), 1.75-1.09 (m, 18H), 1.07-0.95 (m, 6H), 0.94-0.90 (m, 3H), 0.90-0.82 (m, 6H), 0.68 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 165.9, 147.5, 143.5, 139.7, 133.5, 133.3, 129.8, 129.5, 128.46, 128.2, 128.1, 127.7, 127.5, 127.3, 126.9, 125.5, 125.1, 122.8, 74.5, 74.5, 60.6, 56.8, 56.2, 52.7, 50.1, 42.4, 39.8, 39.6, 38.3, 37.1, 36.7, 36.3, 35.9, 32.0, 31.9, 28.3, 28.1, 27.9, 24.4, 23.9, 22.9, 22.7, 21.1, 20.9, 20.8, 19.4, 18.8, 11.9; HRMS (ESI) m / z calcd for C 51 H 66 N2O2[M+H] + = 739.5198, found = 739.5218.

[0103] Example 9

[0104] This example provides a nitrogen-centered chiral base derivative (denoted as chiral compound epimer I-9), which is an enantiomerically pure nitrogen-centered chiral base derivative, and its structural formula is: The preparation method of the compound, the steps are basically the same as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2e (in compound 2e, R 1 = p-crotyl ester group), R configuration chiral phosphoric acid is adjusted to S configuration chiral phosphoric acid, and the remaining steps are the same as those in Example 1. The developing agent is petroleum ether / ethyl acetate = 5 / 1, and the prepared product is chiral compound anti-configuration I-9, 45.6 mg in total, with a yield of 90%, and in the state of colorless oil.

[0105] The analysis data of chiral compound anti-configuration I-9 are as follows: the optical rotation value is -248.2 (concentration is 0.10, solvent is chloroform); HPLC (IJ-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 4.19 min, peak time 2 is 4.41 min, and the enantioselectivity is 90%. The nuclear magnetic characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.00-7.69 (m, 4H), 7.21-7.12 (m, 2H), 7.05-6.98 (m, 2H), 6.79 (s, 1H), 6.45 (s, 1H), 5.51-5.43 (m, 1H), 5.34 (s, 1H), 5.13-5.10 (m, 1H), 4.92-4.69 (m, 3H), 4.34 (d, J = 16.5 Hz, 1H), 4.09 (dd, J = 17.1, 3.0 Hz, 1H), 3.91 (d, J = 17.2 Hz, 1H), 2.26 (s, 3H), 2.11-2.08 (m, 7H), 1.77 (d, J = 2.5 Hz, 3H), 1.69 (s, 3H), 1.62 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 166.6, 147.5, 143.6, 143.5, 142.4, 133.6, 133.3, 131.9, 129.6, 129.5, 128.5, 128.2, 128.1, 127.7, 127.5, 127.3, 126.9, 125.5, 125.1, 123.8, 118.5, 74.5, 61.8, 60.6, 52.7, 39.6, 26.4, 25.8, 20.9, 20.8, 17.8, 16.6; HRMS (ESI) m / z calcd for C 33 H 38 N2O2[M+H] + = 507.3007, found = 507.3009.

[0106] Example 10

[0107] The present embodiment provides a nitrogen center chiral alkali derivative (denoted as chiral compound syn I-10), which is enantiomerically pure nitrogen center chiral alkali derivative, the structural formula is: The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is adjusted to compound 2f (in compound 2f, R 1 = p-diketone galactose ester), the R configuration catalyst is adjusted to the S configuration catalyst, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 50 / 1, and the prepared product is chiral compound syn I-10, 70.9 mg, with a yield of 96%, and in the form of a white solid.

[0108] The analytical data of chiral compound syn I-10 are as follows: the melting point M.p. is 220.0-220.9°C. The optical rotation value is: -190.0 (concentration is 0.10, solvent is chloroform); the diastereomeric selectivity is greater than 20:1. The nuclear magnetic characterization results are: 1 H NMR (400 MHz, CDC13) δ 8.07-7.91 (m, 2H), 7.76-7.55 (m, 2H), 7.24-7.08 (m, 2H), 7.05-6.95 (m, 2H), 6.77 (s, 1H), 6.45 (s, 1H), 5.68-5.48 (m, 1H), 5.32 (s, 1H), 4.80 (d, J = 16.5 Hz, 1H), 4.71-4.60 (m, 1H), 4.56-4.46 (m, 1H), 4.46-4.37 (m, 1H), 4.37-4.26 (m, 3H), 4.23-4.12 (m, 1H), 4.08 (d, J = 17.1 Hz, 1H), 3.90 (d, J = 17.0 Hz, 1H), 2.35-2.20 (m, 3H), 2.18-2.06 (m, 3H), 1.96 (s, 1H), 1.60-1.43 (m, 6H), 1.41-1.40 (m, 6H), 1.27 (s, 1H); 13C NMR (100 MHz, CDC13) δ 166.4, 147.5, 143.8, 143.4, 133.6, 133.3, 129.7, 129.0, 128.5, 128.1, 128.1, 127.7, 127.4, 127.3, 126.9, 125.4, 125.1, 109.7, 108.8, 96.4, 74.5, 71.1, 70.8, 70.6, 66.1, 63.8, 60.6, 52.7, 26.1, 26.0, 25.0, 24.6, 20.9, 20.8; HRMS (ESI) m / z calcd for C 36 H 40 N2O7[M+H] + = 613.2909, found = 613.2910.

[0109] Example 11

[0110] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-11) which is an enantiomerically pure nitrogen center chiral base derivative, having the structure: This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-11) which is an enantiomerically pure nitrogen center chiral base derivative, having the structure:

[0111]

[0112] The preparation method of this compound is basically the same as that of Example 1, except that compound 2a in Example 1 is changed to compound 2c (in compound 2c, R 1 = p-formyl), and compound 1a is changed from 0.1 mmol to 0.24 mmol, and the R configuration chiral phosphoric acid is changed to S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 5 / 1, and the product prepared is chiral compound syn I-11, 41.3 mg in total, with a yield of 72%, in the form of a white solid.

[0113] The analytical data of chiral compound syn I-11 are as follows: the melting point M.p. is 251.1-251.4°C. The optical rotation value is -169.0 (concentration is 0.10, solvent is chloroform); HPLC (IJ-3 chiral column, isopropanol / n-hexane = 20 / 80, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 5.65 min, peak time 2 is 8.79 min, enantiomeric selectivity is > 99%; diastereomeric selectivity is > 20:1. NMR characterization results are as follows: 1 ​H NMR (400 MHz, CDC13) δ 7.44 (s, 4H), 7.15 - 7.03 (m, 4H), 7.01 - 6.89 (m, 4H), 6.74 (s, 2H), 6.43 (s, 2H), 5.26 (s, 2H), 4.74 (d, J = 16.5 Hz, 2H), 4.27 (d, J = 16.6 Hz, 2H), 4.03 (d, J = 16.9 Hz, 2H), 3.84 (d, J = 16.9 Hz, 1H), 2.22 (s, 6H), 2.13 (s, 6H); 13 CNMR (100 MHz, CDC13) δ 147.6, 143.7, 137.4, 133.3, 132.9, 128.2, 128.1, 127.9, 127.7, 127.4, 127.3, 126.9, 125.3, 125.0, 74.6, 60.8, 52.6, 20.9, 20.8; HRMS (ESI) m / z calcd for C 40 H 38 N4[M+H] + = 575.3169, found = 575.3171.

[0114] Example 12

[0115] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-12), which is an enantiomerically pure nitrogen center chiral base derivative, the structural formula is:

[0116] The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is adjusted to compound 2g (in compound 2g, R 1 = m-formyl), and compound 1a is adjusted from 0.1 mmol to 0.24 mmol, and the R configuration chiral phosphoric acid is adjusted to the S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 5 / 1, and the prepared product is chiral compound syn I-12, 37.3 mg in total, with a yield of 65%, in the form of a white solid.

[0117] The analytical data of chiral compound syn I-12 are as follows: the melting point M.p. is 115.3-115.9°C. The optical rotation value is -210.1 (concentration is 0.10, solvent is chloroform); HPLC (IJ-3 chiral column, isopropanol / n-hexane = 20 / 80, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 5.09 min, peak time 2 is 7.61 min, and the enantioselectivity is > 99%. The nuclear magnetic resonance characterization results are:1 H NMR (400 MHz, CDC13) δ 7.96 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 7.16 - 7.10 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.98 (s, 4H), 6.75 (s, 2H), 6.34 (s, 2H), 5.29 (s, 2H), 4.77 (d, J = 16.5 Hz, 2H), 4.29 (d, J = 16.6 Hz, 2H), 3.64 (s, 4H), 2.22 (s, 6H), 2.14 (s, 6H); 13 C NMR (100 MHz, CDC13) δ 147.7, 143.9, 138.2, 133.3, 132.9, 128.3, 128.1, 128.0, 128.0, 127.6, 127.2, 126.7, 126.4, 125.7, 125.2, 74.4, 60.5, 52.5, 21.0, 20.9; HRMS (ESI) m / z calcd for C 40 H 38 N4[M+H] + = 575.3169, found = 575.3168.

[0118] Example 13

[0119] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-13) which is an enantiomerically pure nitrogen center chiral base derivative, having the structure: This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-13) which is an enantiomerically pure nitrogen center chiral base derivative, having the structure:

[0120] The preparation method of this compound is basically the same as that of Example 1, except that compound 2a in Example 1 is changed to compound 2h (in compound 2h, R 1 = p-formylphenyl), and compound 1a is changed from 0.1 mmol to 0.24 mmol, and the R configuration chiral phosphoric acid is changed to S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 10 / 1, and the product prepared is chiral compound syn I-13, 47.5 mg in total, with a yield of 73%, in the form of a white solid.

[0121] ​The analytical data of the chiral compound epimer I-13 are as follows: the melting point M.p. is 115.3-115.9 °C. The optical rotation value is: -180.0 (concentration is 0.10, solvent is chloroform); HPLC (IF-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 5.55 min, peak time 2 is 6.23 min, enantioselectivity is > 99%. The nuclear magnetic characterization results are: 1 H NMR (400 MHz, CDC13) δ 7.59 (d, J = 8.1 Hz, 4H), 7.50-7.40 (m, 4H), 7.18 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.02-6.90 (m, 4H), 6.76 (s, 2H), 6.44 (s, 2H), 5.32 (s, 2H), 4.79 (d, J = 16.5 Hz, 2H), 4.31 (d, J = 16.6 Hz, 2H), 4.15 (d, J = 17.0 Hz, 2H), 3.88 (d, J = 17.0 Hz, 2H), 2.22 (s, 6H), 2.11 (s, 6H); 13 C NMR (100 MHz, CDC13) δ 147.6, 143.7, 139.6, 137.5, 133.4, 133.1, 128.4, 128.2, 128.1, 127.9, 127.7, 127.3, 127.0, 126.8, 125.4, 125.1, 74.5, 60.8, 52.7, 21.0, 20.9; HRMS (ESI) m / z calcd for C 46 H 42 N4[M+H] + = 651.3482, found = 651.3480.

[0122] Example 14

[0123] This example provides a nitrogen-centered chiral base derivative (denoted as chiral compound epimer I-14), which is an enantiopure nitrogen-centered chiral base derivative, having the following structural formula:

[0124]

[0125] The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is replaced by compound 2i (in compound 2i, ), and adjusting compound 1a from 0.1 mmol to 0.24 mmol, adjusting the chiral phosphoric acid of R configuration to the chiral phosphoric acid of S configuration, and the rest of the steps are the same as Example 1. The developing agent is petroleum ether / ethyl acetate = 5 / 1, and the prepared product is chiral compound antipode I-14, 51.6 mg, the yield is 71%, and the state is white solid.

[0126] The analytical data of chiral compound antipode I-14 are as follows: the melting point M.p. > 300℃. The optical rotation value is: -264.2 (the concentration is 0.10, and the solvent is chloroform); HPLC (IF-3 chiral column, isopropanol / n-hexane = 30 / 70, the flow rate is 1.0 mL / min, and the wavelength is 254 nm), internal racemate: the peak time is 7.19 min, main product: the peak time 1 is 6.65 min, the peak time 2 is 7.99 min, and the enantioselectivity is > 99%. The nuclear magnetic characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 4H), 7.60 (s, 4H), 7.54 (d, J = 8.2 Hz, 4H), 7.20 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 8.4 Hz, 4H), 6.79 (s, 2H), 6.49 (s, 2H), 5.36 (s, 2H), 4.82 (d, J = 16.5 Hz, 2H), 4.34 (d, J = 16.6 Hz, 2H), 4.19 (d, J = 17.0 Hz, 2H), 3.91 (d, J = 17.1 Hz, 2H), 2.25 (s, 6H), 2.14 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 147.6, 143.7, 139.7, 139.5, 137.6, 133.4, 133.1, 128.3, 128.2, 128.1, 128.0, 127.7, 127.3, 127.0, 126.8, 125.4, 125.1, 74.5, 60.8, 52.64, 20.9, 20.8; HRMS (ESI) m / z calcd for C 52 H 46 N4[M+H] + = 727.3795, found = 727.3791.

[0127] Example 15

[0128] This example provides a nitrogen center chiral base derivative (denoted as chiral compound antipode I-15), which is an enantiopure nitrogen center chiral base derivative, and the structural formula is as follows:

[0129]

[0130] The preparation method of the compound, the steps are basically the same as example 1, the difference is that the compound 2a in example 1 is adjusted to compound 2j (in compound 2j, ), and the compound 1a is adjusted from 0.1 mmol to 0.24 mmol, the chiral phosphoric acid of R configuration is adjusted to the chiral phosphoric acid of S configuration, and the remaining steps are the same as example 1. The developing agent is petroleum ether / ethyl acetate = 10 / 1, and the prepared product is chiral compound anti-configuration I-15, 51.9 mg, the yield is 77%, and the state is white solid.

[0131] The analytical data of chiral compound anti-configuration I-15 are as follows: the melting point M.p. is 255.4-255.7℃. The optical rotation value is: -134.0 (the concentration is 0.10, and the solvent is chloroform); HPLC (IG-3 chiral column, isopropanol / n-hexane = 10 / 90, the flow rate is 1.0 mL / min, and the wavelength is 254 nm), internal racemic product: the peak time is 7.76 min, main product: peak time 1 is 6.49 min, peak time 2 is 8.74 min, and the enantioselectivity is > 99%. The nuclear magnetic characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 4H), 7.40 (d, J = 8.3 Hz, 4H), 7.15 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.02-6.89 (m, 4H), 6.75 (s, 2H), 6.43 (s, 1H), 5.28 (s, 2H), 4.77 (d, J = 16.6 Hz, 2H), 4.30 (d, J = 16.6 Hz, 2H), 4.09 (d, J = 17.1 Hz, 2H), 3.87 (d, J = 17.1 Hz, 2H), 2.22 (s, 6H), 2.11 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 147.5, 143.5, 138.7, 133.5, 133.2, 131.5, 128.4, 128.2, 128.1, 127.7, 127.6, 127.3, 127.0, 125.4, 125.1, 122.2, 89.4, 74.5, 60.7, 52.7, 20.9, 20.9; HRMS (ESI) m / z calcd for C 48 H 42 N4[M+H] + = 675.3482, found = 675.3485.

[0132] Example 16

[0133] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-16), which is enantiomerically pure nitrogen center chiral base derivative, the structural formula is:

[0134] The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is adjusted to compound 2k (in compound 2k, ), and compound 1a is adjusted from 0.1 mmol to 0.24 mmol, the R configuration chiral phosphoric acid is adjusted to the S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / ethyl acetate = 7 / 1, and the prepared product is chiral compound syn I-16, a total of 48.0 mg, with a yield of 68%, and in the form of a white solid.

[0135] The analytical data of chiral compound syn I-16 are as follows: the melting point M.p. is 201.5-205.4°C. The optical rotation value is: -352.5 (concentration is 0.10, solvent is chloroform); HPLC (AD-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 4.49 min, peak time 2 is 5.14 min, and enantioselectivity is > 99%. The nuclear magnetic characterization results are: 1 H NMR (400 MHz, DMSO) δ 7.89 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.99 (m, 4H), 6.81 (s, 2H), 6.41 (s, 2H), 5.46 (s, 2H), 4.81 (d, J = 16.6 Hz, 2H), 4.27 (d, J = 16.7 Hz, 2H), 3.95 (d, J = 17.3 Hz, 2H), 3.85 (d, J = 17.3 Hz, 2H), 2.19 (s, 6H), 2.04 (s, 6H); 13C NMR (100 MHz, CDC13) δ 187.2, 142.8, 142.4, 138.9, 137.6, 135.9, 134.9, 134.8, 133.4, 130.6, 128.8, 128.4, 125.6, 123.7, 123.5, 123.4, 123.1, 122.9, 122.6, 122.4, 122.3, 120.7, 120.4, 120.3, 69.7, 56.0, 16.2, 16.1; HRMS (ESI) m / z calcd for C 44 H 40 N4[M+H] + = 625.3326, found = 625.3328.

[0136] Example 17

[0137] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-17), which is an enantiomerically pure nitrogen center chiral base derivative, having the structure: This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-17), which is an enantiomerically pure nitrogen center chiral base derivative, having the structure: This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-17), which is an enantiomerically pure nitrogen center chiral base derivative, having the structure:

[0138] The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is adjusted to compound 2l (in compound 2l, R 1 = 3,5-diformyl), and compound 1a is adjusted from 0.1 mmol to 0.36 mmol, and the R configuration chiral phosphoric acid is adjusted to S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The prepared product is chiral compound syn I-17, 14.8 mg in total, with a yield of 18%, in the form of a white solid.

[0139] The analytical data of chiral compound syn I-17 are as follows: the melting point M.p. is 217.2-217.6°C. The optical rotation value is -240.0 (concentration is 0.10, solvent is chloroform); HPLC (IB-3 chiral column, isopropanol / n-hexane = 20 / 80, flow rate is 1.0 mL / min, wavelength is 254 nm), peak time 1 is 3.92 min, peak time 2 is 5.06 min, and the enantioselectivity is >99%. The nuclear magnetic resonance characterization results are as follows: 1H NMR (400 MHz, CDC13) δ 7.76 (s, 3H), 7.26 (d, J = 7.9 Hz, 3H), 7.04 (d, J = 7.9 Hz, 3H), 6.97 (d, J = 8.1 Hz, 3H), 6.92 (d, J = 8.1 Hz, 3H), 6.74 (s, 3H), 6.06 (s, 3H), 5.22 (s, 3H), 4.76 (d, J = 16.6 Hz, 3H), 4.29 (d, J = 16.7 Hz, 3H), 3.13 (d, J = 17.6 Hz, 3H), 2.61 (d, J = 17.6 Hz, 3H), 2.23 (s, 9H), 2.19 (s, 9H); 13 C NMR (100 MHz, CDC13) δ 147.9, 144.1, 137.5, 133.0, 132.6, 128.5, 128.3, 127.9, 127.8, 127.1, 126.9, 126.1, 126.0, 125.3, 73.8, 59.6, 52.3, 21.0, 20.9; HRMS (ESI) m / z calcd for C 57 H 54 N6[M+H] + = 823.4483, found = 823.4481.

[0140] Example 18

[0141] This example provides a nitrogen center chiral base derivative (denoted as chiral compound syn I-18), which is an enantiomerically pure nitrogen center chiral base derivative, having the structure:

[0142]

[0143] The preparation method of the compound is basically the same as that of Example 1, except that compound 2a in Example 1 is adjusted to compound 2m (in compound 2m, R 1 = 3,5-di (p-formylphenyl), and compound la is adjusted from 0.1 mmol to 0.36 mmol, and the R configuration chiral phosphoric acid is adjusted to S configuration chiral phosphoric acid, and the remaining steps are the same as those of Example 1. The developing agent is petroleum ether / dichloromethane / acetone = 5 / 5 / 1, and the prepared product is chiral compound syn I-18, a total of 21 mg, with a yield of 20%, in the form of a white solid.

[0144] The analytical data of the chiral compound epimer I-18 are as follows: the melting point M.p. is 245.3-245.7℃. The optical rotation value is: -78.0 (concentration is 0.10, solvent is chloroform); HPLC (IE-3 chiral column, isopropanol / n-hexane = 20 / 80, flow rate is 1.0 mL / min, wavelength is 254 nm), minor product: peak time 1 is 15.82 min, peak time 2 is 20.34 min, enantioselectivity is >99%; major product: peak time 1 is 13.95 min, peak time 2 is 29.25 min, enantioselectivity is >99%, diastereoselectivity is 7.3:1. The nuclear magnetic characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 6.9 Hz, 9H), 7.54 (d, J = 7.6 Hz, 6H), 7.18 (d, J = 8.1 Hz, 3H), 7.12 (d, J = 8.1 Hz, 3H), 7.05-6.91 (m, 6H), 6.77 (s, 3H), 6.46 (s, 3H), 5.35 (s, 3H), 4.81 (d, J = 16.5 Hz, 3H), 4.32 (d, J = 16.5 Hz, 3H), 4.17 (d, J = 17.0 Hz, 3H), 3.90 (d, J = 17.0 Hz, 3H), 2.23 (s, 9H), 2.12 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 147.6, 143.7, 141.9, 139.9, 137.8, 133.4, 133.1, 128.4, 128.2, 128.1, 127.7, 127.3, 127.1, 127.0, 125.4, 125.1, 124.9, 74.5, 60.8, 52.7, 21.0, 20.9; HRMS (ESI) m / z calcd for C 75 H 66 N6[M+H] + = 1051.5422, found = 1051.5421.

[0145] In conclusion, the preparation method of the nitrogen center chiral alkaline derivative provided by the present application makes the amination reaction of the tetrahydrodibenzo-diazocyclic compound and the aromatic aldehyde more easily occur by taking the chiral phosphoric acid as a catalyst, so that the Λ-shaped alkaline product with wide rigidity is prepared. The present application proves that the preparation idea can be successfully applied to the preparation of more complex three-dimensional structures (such as double alkaline and tri alkaline derivative, which is a nitrogen-centered chiral alkaline molecule, has broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, material science, asymmetric catalysis and drug development. alkaline derivative, which is a nitrogen-centered chiral alkaline molecule, has broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, material science, asymmetric catalysis and drug development.

[0146] The above embodiments are only preferred embodiments of the present application, and cannot be used to limit the scope of protection of the present application. Any non-essential changes and substitutions made by those skilled in the art on the basis of the present application shall fall within the scope of protection of the present application.

Claims

1. A nitrogen-centered chiral A method for preparing alkali derivatives, characterized in that, The process includes the following steps: reacting compound 1, compound 2, additives, and a chiral phosphoric acid catalyst in an organic solvent, followed by purification to obtain a nitrogen-centered chiral compound. Alkali derivatives; Compound 1 is selected from One of them; The structure of compound 2 is shown in Formula II: In Equation II, R 1 Selected from p-bromoyl, p-alkynyl, p-formyl, p-cholesterol ester, p-geraniol ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, One of 3,5-dicarboxyl or 3,5-bis(p-formylphenyl); The chiral phosphoric acid catalyst is an R-configuration chiral phosphoric acid or an S-configuration chiral phosphoric acid; the structural formula of the R-configuration chiral phosphoric acid is: The structural formula of the S-configuration chiral phosphoric acid is: The additive is Molecular sieves; The nitrogen-center chirality The base derivatives are selected from compounds I-1 to I-18 with the following structures:

2. The nitrogen-centered chiral chirality according to claim 1 A method for preparing alkali derivatives, characterized in that, The organic solvent is one or more of chloroform, methane, dichloromethane, and tetrahydrofuran.

3. The nitrogen-centered chirality according to claim 1 or 2 A method for preparing alkali derivatives, characterized in that, The molar ratio of compound 1, compound 2 and the chiral phosphoric acid catalyst is (1–3.6):(1–1.2):(0.04–0.06).

4. The nitrogen-centered chirality according to claim 1 or 2 A method for preparing alkali derivatives, characterized in that, For every 1–3.6 mmol of compound 1, the corresponding amount of additive is 0.9–1.2 g.

5. The nitrogen-centered chirality according to claim 1 or 2 A method for preparing alkali derivatives, characterized in that, The purification was performed using column chromatography.

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