Nitrogen center chiral Trger base derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a nitrogen center chiral imgabs0 # alkali derivative as well as a preparation method and application thereof. According to the preparation method of the nitrogen center chirality # imgabs 1 # alkali derivative provided by the invention, a tetrahydrodibenzodiazepine ring compound is taken as a raw material, and the # imgabs 2 # alkali only having a nitrogen chirality center can be effectively synthesized through an amination reaction catalyzed by chiral phosphoric acid. Moreover, the synthesis method provided by the invention has the advantages of high efficiency, simple steps and strong enantioselectivity, is suitable for industrial production of chiral imgabs3 # alkali and derivatives thereof, and provides a new way for research and application of chiral compounds. Meanwhile, the prepared # imgabs4 # alkali derivative is a # imgabs5 # alkali molecule with nitrogen center chirality, and has wide application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, material science, asymmetric catalysis, drug development and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis and particularly relates to a nitrogen-centered chiral Alkali derivatives and preparation methods and applications thereof. Background Art

[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 properties. As a classic chiral nitrogen compound, TB was first described by Julius It was accidentally obtained in 1887 through the condensation reaction of p-toluidine and formaldehyde. Its structure is a rigid Λ-shaped molecule with C2 symmetry. Since its introduction, TB has become an important model compound in the study of "chiral nitrogen" and is widely used in stereochemistry-related research.

[0003] At present, although the synthesis of TB has a long history of development, it is still challenging to obtain optically pure TB. The main existing TB synthesis method is to resolve racemic TB by high performance liquid chromatography (HPLC) on a chiral stationary phase. However, this method has the problems of low efficiency and high cost, and it is difficult to meet the needs of practical applications. Therefore, the development of a new method for direct and convenient catalytic asymmetric synthesis of TB is of great significance to promote the further expansion and application of TB. Summary of the invention

[0004] In order to overcome the shortcomings of the prior art, the first object of the present invention is to provide a nitrogen-centered chiral Base derivative, which is a chiral nitrogen center Base molecules have broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis and drug development.

[0005] The second object of the present invention is to provide the above nitrogen center chirality The preparation method of the base derivative is simple in process and can prepare a wide range of rigid Λ-shaped base products and can synthesize structurally challenging chiral bicyclic compounds with high enantioselectivity. Alkali and tri Alkali.

[0006] The third object of the present invention is to provide the above nitrogen center chirality Application of base derivatives.

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

[0008] A nitrogen center chirality A base derivative selected from compounds I-1 to I-18 with the following structures:

[0009]

[0010]

[0011]

[0012] The nitrogen center chirality provided by the present invention Base derivative, a chiral nitrogen-centered Base molecules have broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis and drug development.

[0013] The chirality of the nitrogen center The preparation method of the base derivative comprises 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 a nitrogen-centered chiral Base derivatives;

[0014] Wherein, compound 1 is selected from

[0015] One of;

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

[0017]

[0018] In Formula II, R 1 Selected from p-bromo, p-alkynyl, p-formyl, p-cholesterol ester, p-geraniol ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, One of 3,5-diformyl and 3,5-di(p-formylphenyl).

[0019] The nitrogen center chirality provided by the present invention The preparation method of base derivatives, for the first time, uses tetrahydrodibenzodiazepine compounds and aromatic aldehydes as raw materials and successfully applies them to chiral Efficient synthesis of chiral TB and its derivatives. Furthermore, the present invention can effectively synthesize TB having only a nitrogen chiral center through an amination reaction catalyzed by chiral phosphoric acid. The synthesis method provided by the present invention has the advantages of high efficiency, simple steps and strong enantioselectivity, is suitable for the industrial production of chiral TB and its derivatives, and provides a new approach for the research and application of chiral compounds.

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

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

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

[0023] As a preferred embodiment, the additive is Molecular sieve. By using additives, it can remove water and ensure the smooth progress of the reaction.

[0024] As a preferred embodiment, 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 to 3.6 mmol of compound 1, the amount of the corresponding additive is 0.9 to 1.2 g.

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

[0027] The chirality of the nitrogen center Applications of base derivatives in molecular recognition, DNA binding or asymmetric catalysis.

[0028] The above technical solution of the present invention has the following advantages compared with the prior art:

[0029] (1) The preparation method provided by the present invention uses tetrahydrodibenzodiazepine compounds and aromatic aldehydes as starting reaction raw materials, which are cheap and readily available;

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

[0031] (3) The chiral nitrogen center prepared by the present invention The base is obtained in excellent yields and with good enantioselectivity;

[0032] (4) The chiral nitrogen center prepared by the present invention The structural skeleton of the alkali is novel and different from the traditional The types of base compounds form complements;

[0033] (5) The chiral nitrogen center prepared by the present invention Base, has good application value, can form chiral double Alkali or tri Bases have high enantioselectivity and have broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis and drug development. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a graph showing the HPLC result of the racemic compound I-1 in Example 1 of the present invention;

[0035] Figure 2 This is a graph showing the HPLC results of the chiral compound I-1 in Example 1 of the present invention;

[0036] Figure 3 This is a graph showing the HPLC result of the racemic compound I-2 in Example 2 of the present invention;

[0037] Figure 4 This is a graph showing the HPLC results of the chiral compound I-2 in Example 2 of the present invention;

[0038] Figure 5 This is a graph showing the HPLC result of the racemic compound I-3 in Example 3 of the present invention;

[0039] Figure 6 This is a graph showing the HPLC result of the anti-configuration I-3 of the chiral compound in Example 3 of the present invention;

[0040] Figure 7 This is a graph showing the HPLC result of the racemic compound I-4 in Example 4 of the present invention;

[0041] Figure 8 This is a graph showing the HPLC result of the anti-configuration I-4 of the chiral compound in Example 4 of the present invention;

[0042] Fig. 9 This is a graph showing the HPLC result of the racemic compound I-5 in Example 5 of the present invention;

[0043] Fig.10 This is a graph showing the HPLC result of the anti-configuration I-5 of the chiral compound in Example 5 of the present invention;

[0044] Fig.11 This is a graph showing the HPLC result of the racemic compound I-6 in Example 6 of the present invention;

[0045] Fig.12 This is a graph showing the HPLC result of the anti-configuration I-6 of the chiral compound in Example 6 of the present invention;

[0046] Fig.13 This is a graph showing the HPLC result of the racemic compound I-7 in Example 7 of the present invention;

[0047] Fig.14 This is the HPLC result of the anti-configuration I-7 of the chiral compound in Example 7 of the present invention. DETAILED DESCRIPTION

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

[0049] In the present invention, the abbreviations of substituents have the meanings commonly understood in the art, such as "Me" refers to methyl, "F" refers to fluorine, "Cl" refers to chlorine, "Br" refers to bromine, "MeO" refers to methoxy, and "Ph" refers to phenyl.

[0050] In the following examples, the chirality of the nitrogen center is The preparation method of the base derivative comprises 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 a nitrogen-centered chiral Base derivatives.

[0051] Specifically, the chirality of the nitrogen center in Examples 1 to 18 provided below is Method for preparing base derivatives, the prepared nitrogen center chiral The base derivatives are numbered as compounds I-1 to I-18.

[0052] Among them, the compound 1 involved in the following examples is a tetrahydrodibenzodiazepine compound with the structural formula

[0053] They are referred to as Compound 1a to Compound 1e, respectively.

[0054] Furthermore, the compound 1 in the present invention can be prepared by referring to the prior art. Specifically, in the following examples, compounds 1a to 1d can be prepared conventionally based on the existing literature [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 these paration 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 ademonstration of their reactivity to afford methano strap-modified baseanalogues.DOI:10.3998 / ark.5550190.0009.c17.

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

[0058] [3]Carmen Pardo,Céline Pirat,JoséElguero.The synthesis of a linearTrger'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 structure of compound 2 involved in the following examples is shown in Formula II:

[0060]

[0061] In Formula II, R 1 Selected from p-bromo, p-alkynyl, p-formyl, p-cholesterol ester, p-geraniol ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, Specifically, the compounds 2 involved in the following examples are sequentially recorded as compounds 2a to 2m, all of which have the general structural formula shown in Formula II.

[0062] In the following embodiments, the chiral phosphoric acid catalyst is 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, when the racemic compounds in the following examples are prepared, the structural formula of the racemic phosphoric acid catalyst used is:

[0064] Example 1

[0065] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound I-1), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound comprises the following steps:

[0066] Compound 1a (structural formula: 0.1mmol) Molecular sieve (ie 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 1 = p-bromo group, 0.12 mmol), and stirred the reaction at -40°C until the starting material was completely consumed (detected by TLC). The solvent was removed in vacuo, and the crude product was purified by column chromatography, using ethyl acetate / dichloromethane = 10 / 1 as the developing solvent to obtain chiral compound I-1, a total of 38.8 mg, with a yield of 96%, in the form of a white solid.

[0067] Furthermore, a racemic compound I-1 was prepared to compare with the chiral compound I-1 prepared above. The preparation process of the racemic compound I-1 is as follows: Compound 1a (structural formula: 0.1 mmol) and racemic phosphoric acid catalyst (0.005 mmol, 1.75 mg) were dissolved in CHCl3 (1 mL), and compound 2a (R 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 in vacuo and the crude product was separated by flash column chromatography on silica gel to give racemic compound I-1.

[0068] The HPLC result of the racemic compound I-1 prepared in Example 1 of the present invention is shown in FIG. Figure 1 As shown; the HPLC result of chiral compound I-1 is shown in Figure 2 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0069] The analytical data of the chiral compound I-1 of Example 1 are as follows: the melting point Mp is 64.5-64.7°C. The optical rotation value is: +156.0 (concentration is 0.10, solvent is chloroform). The analysis results are: HPLC (IJ chiral column, isopropanol / n-hexane=30 / 70, flow rate is 1.0 mL / min, wavelength is 254 nm), the peak time 1 is 4.61 min, the peak time 2 is 6.45 min, and the enantioselectivity is 96%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.47(d,J=8.4Hz,2H),7.38(d,J=8.5Hz,2H),7.14(d,J=8.1Hz,1H),7.09(d,J=8.2Hz,1H),6.97-6.92(m,2H),6.76(s,1H),6 .45(s,1H),5.22(s,1H),4.77(d,J=16.5Hz,1H),4.29(d,J=16.6Hz,1H), 4.08(d,J=17.0Hz,1H),3.87(d,J=17.0Hz,1H),2.23(s,3H),2.12(s,3H). 13 C NMR (100MHz, CDCl3) δ147.4,143.4,137.6,133.6,133.3,131.4,129.5,128.2,128.1, 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 embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound I-2), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound is basically the same as that of Example 1, except that the compound 1a in Example 1 is adjusted to compound 1b (the structural formula of compound 1b is ), and the remaining steps were the same as in Example 1. The product obtained was chiral compound I-2, 47.5 mg in total, with a yield of 86%, in the form of a white solid.

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

[0073] The HPLC result of the racemic compound I-2 prepared in Example 2 of the present invention is shown in FIG. Figure 3 As shown; the HPLC result of chiral compound I-2 is shown in Figure 4 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0074] The analytical data of the chiral compound I-2 of Example 2 are as follows: the melting point Mp is 68.4-68.8°C. The optical rotation value is: +102.0 (concentration is 0.10, solvent is chloroform). The analysis results are: HPLC (AD chiral column, isopropanol / n-hexane=10 / 90, flow rate is 1.0 mL / min, wavelength is 254 nm), the peak time 1 is 6.17 min, the peak time 2 is 6.76 min, and the enantioselectivity is 96%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.51-7.44(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=16.5Hz,1H),4.45(d,J=16.6Hz,1H),4.22(d,J=17.0Hz,1H),4.04(d,J=17.1Hz,1H). 13 C NMR (100MHz, CDCl3) δ149.4,145.4,140.7,140.6,137.2,137.2,136.9,131.5,129.6,128.8,128.7,128.6,128.1,1 27.1,127.0,126.9,126.8,126.5,126.3,126.1,125.8,125.6,125.2,121.6,74.2,60.8,52.7.HRMS(ESI)m / zcalcd for C 33 H 25 BrN2[M+H] + =529.1274,found=529.1254.

[0075] Example 3

[0076] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-3), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound is basically the same as that of Example 1, except that the compound 1a in Example 1 is adjusted to compound 1c (the structural formula of compound 1c is ), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as in Example 1. The developing solvent was ethyl acetate / ethyl acetate = 20 / 1, and the product obtained was chiral compound anti-configuration I-3, a total of 36.5 mg, a yield of 83%, and a state of white solid.

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

[0078] The HPLC result of the racemic compound I-3 prepared in Example 3 of the present invention is shown in FIG. Figure 5 As shown; the HPLC result of the chiral compound anti-configuration I-3 is shown in FIG. Figure 6 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0079] The analytical data of the chiral compound inverse configuration I-3 of Example 3 are as follows: melting point Mp is 65.2-65.5°C. Optical rotation value is: -231.5 (concentration is 0.10, solvent is chloroform). The analysis results are: 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 enantioselectivity is 90%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.45-7.38(m,J=8.5Hz,4H),6.91(d,J=10.7Hz,1H),6.84(d,J=10.7Hz,1H),6.74(d,J=8.3Hz,1H),6.44(d,J=8.3Hz, 1H),5.18(s,1H),4.71(d,J=16.4Hz,1H),4.25(d,J=16.3Hz,1H),4.03(d,J=16.8Hz,1H),3.83(d,J=16.8Hz,1H),2.15(s,3H),2.05(s,3H). 13C NMR (100MHz, CDCl3) δ160.4 (d, J = 242Hz), 160.3 (d, J = 243Hz), 148.7 (d, J = 10Hz), 14 4.7(d,J=10Hz),131.5,129.4,129.3,129.2(d,J=6Hz),128.9(d,J=6Hz),123.4(d, J=3Hz),122.8(d,J=3Hz),121.6,121.2(d,J=20Hz),121.0(d,J=20Hz),111.5(d,J= 23Hz), 111.3 (d, J = 23Hz), 73.8, 60.0, 52.0, 14.2 (d, J = 3Hz), 14.12, 14.1 (d, J = 3Hz). 19 F NMR(376MHz,CDCl3)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] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-4), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound is basically the same as that of Example 1, except that the compound 1a in Example 1 is adjusted to compound 1d (the structural formula of compound 1d is ), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as in Example 1. The developing solvent was ethyl acetate / ethyl acetate = 2 / 1, and the product prepared was chiral compound anti-configuration I-4, a total of 5.6 mg, a yield of 92%, and a state of white solid.

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

[0083] The HPLC result of the racemic compound I-4 prepared in Example 4 of the present invention is shown in FIG. Figure 7 As shown; the HPLC result of the chiral compound anti-configuration I-4 is shown in Figure 8 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0084] The analytical data of the chiral compound trans-configuration I-4 of Example 4 are as follows: melting point Mp is 156.2-156.7°C. Optical rotation value is: -100.3 (concentration is 0.10, solvent is chloroform). The analysis results are: 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 enantioselectivity is 90%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.46-7.39(m,4H),6.79-6.73(m,2H),6.44(s,1H),6.14(s,1H),5.20(d,J=3.4Hz,1H),4.7 4(d,J=15.9Hz,1H),4.28(d,J=16.1Hz,1H),4.00(d,J=16.7Hz,1H),3.93-3.85(m,7H),3.79(s,3H),3.68(s,3H). 13 C NMR (100MHz, CDCl3) δ148.6,148.4,146.3,146.0,142.5,138.3,137.5,131.3,129.4,121 .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 embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-5) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound is basically the same as that of Example 1, except that the compound 1a in Example 1 is adjusted to compound 1e (the structural formula of compound 1e is ), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as Example 1. The developing solvent was ethyl acetate / ethyl acetate = 2 / 1, and the product prepared was chiral compound anti-configuration I-5, a total of 45.6 mg, a yield of 92%, and a state of white solid.

[0087] Referring to the preparation method of the racemic compound I-1 in Example 1, the compound 1a was adjusted to the compound 1e, and the other conditions remained unchanged to prepare the racemic compound I-5.

[0088] The HPLC result of the racemic compound I-5 prepared in Example 5 of the present invention is shown in FIG. Fig. 9 As shown; the HPLC result of the chiral compound anti-configuration I-5 is shown in Fig.10 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0089] The analytical data of the chiral compound trans-configuration I-5 of Example 5 are as follows: melting point Mp is 72.1-72.6°C. Optical rotation value is: -105.0 (concentration is 0.10, solvent is chloroform). The analysis results are: 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 enantioselectivity is 84%. NMR characterization results: 1 H NMR(400MHz, CDCl3)δ7.79(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=16.5Hz,1H),4.76(d,J=16.6Hz,1H),4.51(d,J=17.1Hz,1H),4.33(d,J=17.1Hz,1H). 13 C NMR (100MHz, CDCl3) δ148.6,145.1,137.3,133.3,133.1,131.5,130.8,130.6,129.6,127.9,127.4,127.2,1 27.1,126.8,125.7,125.6,125.5,125.1,125.0,124.9,122.9,122.4,121.6,74.3,62.7,54.4.HRMS(ESI)m / z calcd for C 29 H 21 BrN2[M+H] + =477.0961,found=477.0965.

[0090] Example 6

[0091] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-6), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2b (in compound 2b, R 1 = para-alkynyl), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as Example 1. The developing solvent was petroleum ether / dichloromethane = 5 / 1, and the product obtained was chiral compound anti-configuration I-6, a total of 31.5 mg, a yield of 90%, and a state of white solid.

[0092] Referring to the preparation method of the racemic compound I-1 in Example 1, the compound 2a was adjusted to the compound 2b, and the other conditions remained unchanged to prepare the racemic compound I-6.

[0093] The HPLC result of the racemic compound I-6 prepared in Example 6 of the present invention is shown in FIG. Fig.11 As shown; the HPLC result of the chiral compound trans-configuration I-6 is shown in Fig.12 As shown in the HPLC result chart, it can be seen that the chiral compound of the present invention was successfully prepared.

[0094] The analytical data of the chiral compound inverse configuration I-6 of Example 6 are as follows: melting point Mp is 164.6-164.9°C. Optical rotation value is: -370.1 (concentration is 0.10, solvent is chloroform). The analysis results are: 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 enantioselectivity is 92%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.57-7.54(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=3.7Hz,1H),4.76(m,1H) ,4.29(dd,J=16.7,3.7Hz,1H),4.08(dd,J=17.1,5.1Hz,1H),3.87(dd,J=17.1, 4.5Hz, 1H), 3.00 (d, J = 3.8Hz, 1H), 2.21 (d, J = 3.2Hz, 3H), 2.10 (d, J = 2.9Hz, 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 center chirality Base derivative (denoted as chiral compound trans-configuration I-7), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2c (in compound 2c, R 1 = p-formyl), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as Example 1. The developing solvent was petroleum ether / ethyl acetate = 5 / 1, and the product obtained was chiral compound anti-configuration I-7, a total of 30.8 mg, with a yield of 87%, in the form of a white solid.

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

[0098] The HPLC result of the racemic compound I-7 prepared in Example 7 of the present invention is shown in FIG. Fig.13 As shown; the HPLC result of the chiral compound trans-configuration I-7 is shown in Fig.14 As shown. It can be seen from the HPLC result chart that the chiral compound of the present invention was successfully prepared. The following Examples 8 to 18 can obtain similar comparison results of racemic compounds and chiral compounds, which will not be repeated in the present invention.

[0099] The analytical data of the chiral compound inverse configuration I-7 of Example 7 are as follows: melting point Mp is 53.2-53.9°C. Optical rotation value is: -262.2 (concentration is 0.10, solvent is chloroform). The analysis results are: 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 enantioselectivity is 90%. NMR characterization results: 1 H NMR(400MHz, CDCl3)δ9.92(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=16.5Hz,1H),4.32(d,J=16.5Hz,1H),4.07(d,J=17.1Hz,1H),3.90(d,J=17.1Hz,1H),2.23(s,3H),2.12(s,3H); 13 C NMR (100MHz, CDCl3) δ192.1,147.4,145.4,143.3,135.5,133.7,133.4,129.7,128.6,128.4, 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 embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-8), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2d (in compound 2d, R 1 = para-cholesterol ester group), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as Example 1. The developing solvent was petroleum ether / ethyl acetate = 100 / 1, and the product obtained was chiral compound anti-configuration I-8, a total of 70.9 mg, a yield of 96%, and a state of white solid.

[0102] The analytical data of the chiral compound anti-configuration I-8 are as follows: melting point Mp is 198.3-198.6°C. Optical rotation value is: -158.1 (concentration is 0.10, solvent is chloroform); diastereoselectivity is greater than 20:1. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.2Hz,2H),7.67(d,J=7.9Hz,2H),7.16(d,J=8.1Hz,1H),7.10(d,J=8.1Hz, 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 .6Hz,1H),4.07(d,J=17.1Hz,1H),3.88(d,J=17.1Hz,1H),2.43(d,J=7.5Hz,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 (100MHz, CDCl3) δ165.9,147.5,143.5,139.7,133.5,133.3,129.8,129.5,128.46 ,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 forC 51 H 66 N2O2[M+H] + =739.5198,found=739.5218.

[0103] Example 9

[0104] This embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-9) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is: The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2e (in compound 2e, R 1 = p-geraniol ester), R-configuration chiral phosphoric acid was adjusted to S-configuration chiral phosphoric acid, and the remaining steps were the same as Example 1. The developing solvent was petroleum ether / ethyl acetate = 5 / 1, and the product obtained was chiral compound anti-configuration I-9, a total of 45.6 mg, a yield of 90%, and a state of colorless oil.

[0105] The analysis data of the chiral compound anti-configuration I-9 are as follows: optical rotation value: -248.2 (concentration 0.10, solvent chloroform); HPLC (IJ-3 chiral column, isopropanol / n-hexane = 30 / 70, flow rate 1.0 mL / min, wavelength 254 nm), peak time 1 is 4.19 min, peak time 2 is 4.41 min, and enantioselectivity is 90%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ8.00-7.69(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=16.5Hz,1H),4.09(dd,J=17.1,3.0Hz,1H),3.91(d,J=17.2Hz,1H ),2.26(s,3H),2.11-2.08(m,7H),1.77(d,J=2.5Hz,3H),1.69(s,3H),1.62(s,3H); 13 C NMR (100MHz, CDCl3) δ166.6,147.5,143.6,143.5,142.4,133.6,133.3,131.9,129.6,129.5,128.5,128.2,128.1,127.7,127 .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] This embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-10) is an enantiomerically pure nitrogen-centered chiral Base derivatives, 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 = for diacetone galactose ester), the R-configuration catalyst was adjusted to the S-configuration catalyst, and the remaining steps were the same as Example 1. The developing solvent was petroleum ether / ethyl acetate = 50 / 1, and the product obtained was the chiral compound trans-configuration I-10, a total of 70.9 mg, a yield of 96%, and a state of white solid.

[0108] The analytical data of the chiral compound anti-configuration I-10 are as follows: melting point Mp is 220.0-220.9°C. Optical rotation value is: -190.0 (concentration is 0.10, solvent is chloroform); diastereoselectivity is greater than 20:1. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ8.07-7.91(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=16.5Hz,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),4.23-4.1 2(m,1H),4.08(d,J=17.1Hz,1H),3.90(d,J=17.0Hz,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 (100MHz, CDCl3) δ166.4,147.5,143.8,143.4,133.6,133.3,129.7,129.0,128.5,128.1,128.1,127.7,127.4,127.3,126.9,1 25.4,125.1,109.7,108.8,96.4,74.5,71.1,70.8,70.6,66.1,63.8,60.6,52.7,26.1,26.0,25.0,24.6,20.9,20.8; HRMS(ESI)m / z calcd forC 36 H 40 N2O7[M+H] + =613.2909,found=613.2910.

[0109] Embodiment 11

[0110] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-11), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

[0111]

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

[0113] The analytical data of the chiral compound anti-configuration I-11 are as follows: melting point Mp is 251.1-251.4°C. 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 1.0mL / min, wavelength is 254nm), peak time 1 is 5.65min, peak time 2 is 8.79min, enantioselectivity is>99%; diastereoselectivity>20:1;. NMR characterization results: 1H NMR (400MHz, CDCl3) δ7.44 (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=16.5Hz,2H), 4.27(d,J=16.6Hz,2H),4.03(d,J=16.9Hz,2H),3.84(d,J=16.9Hz,1H),2.22(s,6H),2.13(s,6H); 13 CNMR (100MHz, CDCl3) δ147.6,143.7,137.4,133.3,132.9,128.2,128.1,127.9,127 .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 embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-12) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

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

[0117] The analytical data of the chiral compound anti-configuration I-12 are as follows: melting point Mp is 115.3-115.9°C. 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, enantioselectivity>99%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.39 (d, J = 7.6Hz, 2H), 7.19 (d, J = 8.2Hz, 2H), 7.16 -7.10(m,1H),7.03(d,J=8.1Hz,2H),6.98(s,4H),6.75(s,2H),6.34(s,2H),5.29(s,2H) ,4.77(d,J=16.5Hz,2H),4.29(d,J=16.6Hz,2H),3.64(s,4H),2.22(s,6H),2.14(s,6H); 13 C NMR (100MHz, CDCl3) δ147.7,143.9,138.2,133.3,132.9,128.3,128.1,128.0,128.0, 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 embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-13) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

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

[0121] The analytical data of the chiral compound anti-configuration I-13 are as follows: melting point Mp is 115.3-115.9°C. 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>99%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.59(d,J=8.1Hz,4H),7.50-7.40(m,4H),7.18(d,J=8.1Hz,2H),7.11(d,J=8.1Hz,2H),7.02-6.90(m,4H),6.76(s,2H),6.4 4(s,2H),5.32(s,2H),4.79(d,J=16.5Hz,2H),4.31(d,J=16.6Hz,2H),4 .15(d,J=17.0Hz,2H),3.88(d,J=17.0Hz,2H),2.22(s,6H),2.11(s,6H); 13 C NMR (100MHz, CDCl3) δ147.6,143.7,139.6,137.5,133.4,133.1,128.4,128.2,128.1,127 .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] Embodiment 14

[0123] This embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-14), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

[0124]

[0125] The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2i (in compound 2i, ), while adjusting compound 1a from 0.1 mmol to 0.24 mmol, and adjusting R-configuration chiral phosphoric acid to S-configuration chiral phosphoric acid, the remaining steps are the same as Example 1. The developing solvent is petroleum ether / ethyl acetate = 5 / 1, and the product prepared is chiral compound anti-configuration I-14, a total of 51.6 mg, with a yield of 71%, in the form of a white solid.

[0126] The analytical data of the chiral compound anti-configuration I-14 are as follows: melting point Mp>300°C. Optical rotation value: -264.2 (concentration is 0.10, solvent is chloroform); HPLC (IF-3 chiral column, isopropanol / n-hexane=30 / 70, flow rate is 1.0mL / min, wavelength is 254nm), meso product: elution time is 7.19min, main product: elution time 1 is 6.65min, elution time 2 is 7.99min, enantioselectivity>99%. NMR characterization results: 1 H NMR(400MHz, CDCl3) δ7.65(d,J=8.1Hz,4H),7.60(s,4H),7.54(d,J=8.2Hz,4 H),7.20(d,J=8.1Hz,2H),7.13(d,J=8.1Hz,2H),7.00(t,J=8.4Hz,4H),6.79( s,2H),6.49(s,2H),5.36(s,2H),4.82(d,J=16.5Hz,2H),4.34(d,J=16.6Hz,2 H),4.19(d,J=17.0Hz,2H),3.91(d,J=17.1Hz,2H),2.25(s,6H),2.14(s,6H); 13 C NMR (100MHz, CDCl3) δ147.6,143.7,139.7,139.5,137.6,133.4,133.1,128.3,128.2,128.1,1 28.0,127.7,127.3,127.0,126.8,125.4,125.1,74.5,60.8,52.64,20.9,20.8; HRMS(ESI)m / z calcd for C 52 H 46 N4[M+H] + =727.3795,found=727.3791.

[0127] Embodiment 15

[0128] This embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-15) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

[0129] .

[0130] The preparation method of the compound has the same steps as those in Example 1, except that the compound 2a in Example 1 is adjusted to compound 2j (in compound 2j, ), while adjusting compound 1a from 0.1 mmol to 0.24 mmol, and adjusting R-configuration chiral phosphoric acid to S-configuration chiral phosphoric acid, the remaining steps are the same as Example 1. The developing solvent is petroleum ether / ethyl acetate = 10 / 1, and the product prepared is chiral compound anti-configuration I-15, totaling 51.9 mg, with a yield of 77%, in the form of a white solid.

[0131] The analytical data of the chiral compound anti-configuration I-15 are as follows: melting point Mp is 255.4-255.7°C. Optical rotation value is: -134.0 (concentration is 0.10, solvent is chloroform); HPLC (IG-3 chiral column, isopropanol / n-hexane=10 / 90, flow rate is 1.0 mL / min, wavelength is 254 nm), meso product: peak time is 7.76 min, main product: peak time 1 is 6.49 min, peak time 2 is 8.74 min, enantioselectivity>99%. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.55(d,J=8.1Hz,4H),7.40(d,J=8.3Hz,4H),7.15(d,J=8.1Hz,2H),7.09(d,J=8.2Hz,2H),7.02-6.89(m,4H),6.75(s,2H),6 .43(s,1H),5.28(s,2H),4.77(d,J=16.6Hz,2H),4.30(d,J=16.6Hz,2H), 4.09(d,J=17.1Hz,2H),3.87(d,J=17.1Hz,2H),2.22(s,6H),2.11(s,6H); 13C NMR (100MHz, CDCl3) δ147.5,143.5,138.7,133.5,133.2,131.5,128.4,128.2,128.1,127.7, 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 embodiment provides a nitrogen center chirality Base derivative (denoted as chiral compound trans-configuration I-16), which is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

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

[0135] The analytical data of the chiral compound anti-configuration I-16 are as follows: melting point Mp is 201.5-205.4°C. 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, enantioselectivity>99%. NMR characterization results: 1H NMR (400MHz, DMSO) δ7.89(d,J=8.3Hz,2H),7.75(d,J=8.5Hz,2H),7.68(d,J= 8.7Hz,2H),7.24(d,J=8.1Hz,2H),7.13(d,J=8.1Hz,2H),6.99(m,4H),6.81(s ,2H),6.41(s,2H),5.46(s,2H),4.81(d,J=16.6Hz,2H),4.27(d,J=16.7Hz,2 H),3.95(d,J=17.3Hz,2H),3.85(d,J=17.3Hz,2H),2.19(s,6H),2.04(s,6H); 13 C NMR (100MHz, CDCl3) δ187.2,142.8,142.4,138.9,137.6,135.9,134.9,134.8,133.4,130.6,128.8,128.4,125.6,1 23.7,123.5,123.4,123.1,122.9,122.6,122.4,122.3,120.7,120.4,120.3,69.7,56.0,16.2,16.1; HRMS(ESI)m / z calcd for C 44 H 40 N4[M+H] + =625.3326,found=625.3328.

[0136] Embodiment 17

[0137] This embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-17) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

[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 21 (in Compound 21, R 1 =3,5-diformyl), and at the same time, the compound 1a was adjusted from 0.1mmol to 0.36mmol, 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 / dichloromethane / ethyl ether = 5 / 5 / 1. The product prepared was the chiral compound anti-configuration I-17, a total of 14.8mg, the yield was 18%, and the state was white solid.

[0139] The analytical data of the chiral compound anti-configuration I-17 are as follows: melting point Mp is 217.2-217.6°C. 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, enantioselectivity is >99%;. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.76(s,3H),7.26(d,J=7.9Hz,3H),7.04(d,J=7.9Hz,3H),6.97(d,J=8.1Hz,3H),6.92(d,J=8.1Hz,3H),6.74(s,3H),6.06 (s,3H),5.22(s,3H),4.76(d,J=16.6Hz,3H),4.29(d,J=16.7Hz,3H),3.13(d,J=17.6Hz,3H),2.61(d,J=17.6Hz,3H),2.23(s,9H),2.19(s,9H); 13 C NMR (100MHz, CDCl3) δ147.9,144.1,137.5,133.0,132.6,128.5,128.3,127.9,127 .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] Embodiment 18

[0141] This embodiment provides a nitrogen center chirality The base derivative (denoted as chiral compound trans-configuration I-18) is an enantiomerically pure nitrogen-centered chiral Base derivatives, the structural formula is:

[0142]

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

[0144] The analytical data of the chiral compound anti-configuration I-18 are as follows: melting point Mp is 245.3-245.7°C. 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: elution time 1 is 15.82 min, elution time 2 is 20.34 min, enantioselectivity is >99%; major product: elution time 1 is 13.95 min, elution time 2 is 29.25 min, enantioselectivity is >99%, diastereoselectivity is 7.3:1. NMR characterization results: 1 H NMR (400MHz, CDCl3) δ7.65(d,J=6.9Hz,9H),7.54(d,J=7.6Hz,6H),7.18(d,J=8.1Hz,3H),7.12(d,J=8.1Hz,3H),7.05-6.91(m,6H),6.77(s,3H),6 .46(s,3H),5.35(s,3H),4.81(d,J=16.5Hz,3H),4.32(d,J=16.5Hz,3H), 4.17(d,J=17.0Hz,3H),3.90(d,J=17.0Hz,3H),2.23(s,9H),2.12(s,9H); 13 C NMR (100MHz, CDCl3) δ147.6,143.7,141.9,139.9,137.8,133.4,133.1,128.4,128.2,128.1, 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 summary, the chirality of the nitrogen center provided by the present invention The method for preparing a base derivative is to use chiral phosphoric acid as a catalyst to make the amination reaction of a tetrahydrodibenzodiazepine compound with an aromatic aldehyde easier to occur, thereby preparing a Λ-shaped base derivative with a wide range of rigidity. The base product has high yield and good enantioselectivity (yield up to 96%, ee up to> 99%), and the present invention proves that the preparation idea can be successfully applied to the preparation of more complex three-dimensional structures (such as bi Alkali and tri The above contents all confirm that the chiral nitrogen center prepared by the present invention Base derivative, which is a chiral nitrogen center Base molecules have broad application prospects in the fields of molecular recognition, DNA binding, supramolecular chemistry, materials science, asymmetric catalysis and drug development.

[0146] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A nitrogen center chirality A base derivative, characterized in that Compounds I-1 to I-18 selected from the following structures:

2. A nitrogen center chiral A method for preparing a base derivative, characterized in that: The method comprises the following steps: reacting compound 1, compound 2, an additive and a chiral phosphoric acid catalyst in an organic solvent, and then purifying the mixture to obtain a nitrogen-centered chiral Base derivatives; Wherein, compound 1 is selected from One of; The structure of compound 2 is shown in formula II: In Formula II, R 1 Selected from p-bromo, p-alkynyl, p-formyl, p-cholesterol ester, p-geraniol ester, p-diacetone galactose ester, m-formyl, p-formylphenyl, One of 3,5-diformyl and 3,5-di(p-formylphenyl).

3. The nitrogen center chirality according to claim 2 A method for preparing a base derivative, characterized in that: The chiral phosphoric acid catalyst is R-configuration chiral phosphoric acid or S-configuration chiral phosphoric acid.

4. The nitrogen center chirality according to claim 3 A method for preparing a base derivative, characterized in that: The structural formula of the R-configuration chiral phosphoric acid is: The structural formula of the S-configuration chiral phosphoric acid is:

5. The nitrogen center chirality according to claim 2 A method for preparing a base derivative, characterized in that: The organic solvent is one or more of chloroform, methane, dichloromethane and tetrahydrofuran.

6. The nitrogen center chirality according to claim 2 A method for preparing a base derivative, characterized in that: The additive is Molecular sieve.

7. The nitrogen-centered chiral A method for preparing a base derivative, characterized in that: The molar ratio of compound 1, compound 2 and chiral phosphoric acid catalyst is (1-3.6):(1-1.2):(0.04-0.06).

8. The nitrogen-centered chiral A method for preparing a base derivative, characterized in that: For every 1 to 3.6 mmol of compound 1, the amount of the corresponding additive is 0.9 to 1.2 g.

9. The nitrogen-centered chiral A method for preparing a base derivative, characterized in that: The purification is performed by column chromatography.

10. A nitrogen-centered chiral The use of the base derivative is characterized in that Applications in molecular recognition, DNA binding or asymmetric catalysis.

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