A process for the preparation of 1,4-diazabicyclooctane

Abstract

The application discloses a preparation method of 1,4-diazocane, which comprises the following steps: reacting an imidazoline compound with a cyclopropane compound in the presence of a Lewis acid catalyst and an organic solvent to obtain a compound with a structure shown in formula I: wherein R1 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaromatic group, substituted or unsubstituted C 2‑10 alkenyl, substituted or unsubstituted C 2‑10 alkynyl and substituted or unsubstituted C 1～6 alkyl; R2 is selected from C 2～10 ester group and nitrile group; and R3 is selected from substituted or unsubstituted phenyl. According to the application, the 1,4-diazocane is prepared through [5+3] cyclization of the imidazoline compound and the cyclopropane compound under the action of the Lewis acid catalyst, the raw material is cheap and easy to obtain, the operation is convenient, and the yield is high.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 1,4-diazaoctane. Background Technology

[0002] Saturated 1,4-diazahexacycles, including piperazines, 1,4-diazaheptanes, and 1,4-diazaoctanes, are widely present as key structures in a large number of drugs, such as indinavir, aripiprazole, gatifloxacin, suvorexant, Fasudil, and Benzolactam-V8. Compared to six-membered piperazines and seven-membered 1,4-diazaheptanes, the synthesis of eight-membered 1,4-diazaoctanes faces significant challenges, with few reported reactions for efficient synthesis. Furthermore, all existing reactions have limitations: demanding reaction conditions, difficult starting material synthesis, generally low yields, poor functional group compatibility, and currently, no reports on the synthesis of chiral 1,4-diazaoctanes.

[0003] Therefore, there is an urgent need to develop an efficient and simple method to rapidly construct 1,4-diazaoctane from readily available starting materials. Summary of the Invention

[0004] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides a method for preparing 1,4-diazaoctane.

[0005] A method for preparing 1,4-diazaoctane according to a first aspect embodiment of the present invention includes the following steps:

[0006] The imidazoline compound with the structure shown in Formula II was reacted with the cyclopropane compound with the structure shown in Formula III in the presence of a Lewis acid catalyst and an organic solvent to obtain the compound with the structure shown in Formula I:

[0007]

[0008] Wherein, R1 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted C groups. 2-10 alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 1～6 Alkyl groups;

[0009] R2 is selected from C 2～10 The ester group and nitrile group;

[0010] R3 is selected from substituted or unsubstituted phenyl groups.

[0011] The preparation method according to embodiments of the present invention has at least the following beneficial effects:

[0012] This invention relates to the preparation of 1,4-diazaoctane by [5+3] cyclization of imidazoline compounds and cyclopropane compounds under the action of Lewis acid catalysts. The raw materials for this synthesis are inexpensive and readily available, the operation is convenient, and the yield is high, providing a simple and efficient method for the preparation of 1,4-diazaoctane.

[0013] The mechanism is as follows:

[0014]

[0015] According to some embodiments of the present invention, the Lewis acid catalyst is selected from at least one of trifluoromethanesulfonate metal salt or perchlorate metal salt.

[0016] According to some embodiments of the present invention, the trifluoromethanesulfonate metal salt is selected from at least one of copper trifluoromethanesulfonate, cuprous trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, or scandium trifluoromethanesulfonate.

[0017] According to some embodiments of the present invention, the perchlorate metal salt is selected from at least one of copper perchlorate hexahydrate, cobalt perchlorate hexahydrate, or nickel perchlorate hexahydrate.

[0018] According to some embodiments of the present invention, the organic solvent is selected from at least one of dichloromethane, trichloromethane, toluene, tetrahydrofuran, or dichloroethane.

[0019] According to some embodiments of the present invention, the molar ratio of the imidazoline compound of Formula II, the cyclopropane compound of Formula III, and the Lewis acid catalyst is 1:(1-5):(0.1-0.2).

[0020] According to some embodiments of the present invention, the raw materials in the preparation method further include a side-arm bisoxazoline ligand. Therefore, when a side-arm bisoxazoline ligand is added to the raw materials, the prepared product is a chiral 1,4-diazaoctane, with the following structural formula:

[0021]

[0022] According to some embodiments of the present invention, the sidearm bisoxazoline ligand is selected from one of the following structural formulas:

[0023]

[0024] According to some embodiments of the present invention, the molar ratio of the imidazoline compound of Formula II, the cyclopropane compound of Formula III, the Lewis acid catalyst, and the sidearm bisoxazoline ligand is 1:(1-5):(0.1-0.2):(0.12-0.24).

[0025] According to some embodiments of the present invention, the reaction temperature is -70°C to 60°C. Further, when the raw materials do not contain the side-arm bisoxazoline ligand, the reaction temperature is 0°C to 60°C. When the raw materials contain the side-arm bisoxazoline ligand, the reaction temperature is -60°C to 0°C.

[0026] According to some embodiments of the present invention, the reaction time is 2 to 72 hours.

[0027] Definitions and general terms

[0028] "Substituted or unsubstituted aryl" means an all-carbon monocyclic or fused polycyclic group having a fully conjugated π-electron system, and optionally at least one H in the aryl group (e.g., phenyl, naphthyl) is substituted by a corresponding group as defined herein. The substitution is monosubstituted or polysubstituted, and the substituent is selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, halogen, and nitro groups.

[0029] "Substituted or unsubstituted heteroaromatic group" refers to a monocyclic or fused cyclic group containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining cyclic atoms being C, and possessing a fully conjugated π-electron system. For example, the heteroaromatic group is selected from indole, benzothiophene, benzofuran, thiophene, furan, pyrazole, etc.; the substitution is monosubstituted or polysubstituted, and the substituent is selected from C. 1～6 alkyl, C 1～6 alkoxy, C 1～6 Halogenated alkyl groups, halogens, and nitro groups.

[0030] "C replaced or not replaced" 2-10 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds, and the total number of carbon atoms in the group is 2-10. The double bonds in the group can be in any position and can be selected from C1 to C2. 2-10 At least one H in the alkenyl group is replaced by a corresponding group as defined herein. The substituent is selected from C1. 1～6 Alkyl and phenyl groups.

[0031] "C replaced or not replaced" 2-10 The term "alkynyl" has a similar definition, wherein at least one H in an alkynyl group optionally ranging from C2 to C10 is replaced by a corresponding group as defined herein. The substituent is selected from C10 groups. 1～6 Alkyl, phenyl, heteroaryl groups.

[0032] "Substituted or unsubstituted phenyl" has a similar definition, wherein at least one H in the phenyl group is optionally substituted by a corresponding group as defined herein. The substituent is selected from C1-6 alkyl, halogen, saturated heterocyclic, nitro, trifluoromethyl, and C1-6 alkoxy groups.

[0033] "C replaced or not replaced" 1～6 "alkyl" refers to an alkyl group with a total number of carbon atoms of 1-6, including C1-6 straight-chain alkyl, C1-6 branched alkyl, and C3-6 cycloalkyl. For example, it can be a straight-chain alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6; a branched alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6; or a cycloalkyl group with a total number of carbon atoms of 3, 4, 5, or 6. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. Optionally, at least one H in this group is replaced by a corresponding group as defined herein. The substituent is selected from halogens, nitro groups, phenyl groups, and heteroaryl groups.

[0034] “C 2～10 The term "ester group" refers to an ester group with a total number of carbon atoms of 2 to 10. Representative examples include methyl formate, ethyl formate, ethyl acetate, methyl acetate, isopropyl formate, benzyl formate, and tert-butyl formate.

[0035] "Halogen" includes any one or more of fluorine, chlorine, bromine, and iodine.

[0036] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0037] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0038] Figure 1 The HPLC spectrum of product Ib-a chirality obtained in Example 12 of this invention;

[0039] Figure 2 This is the HPLC spectrum of product Ib-b chirality obtained in Example 19 of the present invention;

[0040] Figure 3 The HPLC spectrum of the chirality of product Ib-c obtained in Example 20 of this invention;

[0041] Figure 4The HPLC spectrum of the chirality of product Ib-d obtained in Example 21 of this invention;

[0042] Figure 5 The HPLC spectrum of the chirality of product Ib-e obtained in Example 22 of this invention;

[0043] Figure 6 The HPLC spectrum of product Ib-f chirality obtained in Example 23 of this invention;

[0044] Figure 7 The HPLC spectrum of product Ib-g obtained in Example 24 of this invention is shown.

[0045] Figure 8 The HPLC spectrum of product Ib-h obtained in Example 25 of this invention is shown.

[0046] Figure 9 The HPLC spectrum of the product Ib-i chirality obtained in Example 26 of this invention;

[0047] Figure 10 The HPLC spectrum of product Ib-j ​​obtained in Example 27 of this invention is shown.

[0048] Figure 11 The HPLC spectrum of product Ib-k chirality obtained in Example 28 of this invention;

[0049] Figure 12 The HPLC spectrum of the chirality of product Ib-l obtained in Example 29 of this invention;

[0050] Figure 13 This is the HPLC spectrum of the chirality of product Ib-m obtained in Example 30 of the present invention. Detailed Implementation

[0051] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0052] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0053] Example 1

[0054] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-n), the steps of which are as follows:

[0055]

[0056] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3n (70 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-n (86 mg, yield: 83%).

[0057] Examples 2-11 and Comparative Examples 1-3

[0058] Examples 2-11 and Comparative Examples 1-3 provide a series of methods for preparing 1,4-diazaoctane (Ia-a), the preparation methods of which are basically the same as those in Example 1. The differences and results between Examples 2-11 and Example 1 are shown in Table 1.

[0059] Table 1

[0060]

[0061]

[0062] Example 12

[0063] Example 12 provides a method for preparing 1,4-diazaoctane (Ⅰa-a), which is a racemic product, and the steps are as follows:

[0064]

[0065] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3a (79 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-a (60 mg, yield: 55%).

[0066] Furthermore, a method for preparing chiral 1,4-diazaoctane (Ib-a) is also provided, comprising the following steps:

[0067]

[0068] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and the side-arm bisoxazoline ligand L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction system was then transferred to a -40°C cryogenic reactor, where cyclopropane 3a (79 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-a (82 mg, yield: 75%, enantioselectivity: 95%).

[0069] The test data for product Ib-a are as follows: 1 H NMR (500MHz, CDCl3): δ7.07–7.00(m,2H),6.85–6.71(m,8H),6.64–6.57(m,2H),4 .65(dd,J=12.5,2.9Hz,1H),4.38(d,J=15.6Hz,1H),3.98–3.88(m,2H),3.80–3.76 (m,6H),3.75–3.72(m,6H),3.69(d,J=15.6Hz,1H),3.65–3.57(m,1H),3.50(s,3H ),3.39–3.32(m,1H),2.88(dd,J=15.4,12.7Hz,1H),2.67(dd,J=15.4,2.9Hz,1H); 13 C NMR (125MHz, CDCl3): δ172.2,171.0,158.5,153.3,151.4,144.9,142.8,133.9,127.8,118.8, 115.0,114.6,114.1,113.2,58.7,56.4,55.8,55.7,55.4,54.5,54.3,52.9,52.7,48.7,36.1.

[0070] The chiral product 1,4-diazaoctane (Ⅰb-a) was analyzed by HPLC, and the results are as follows: Figure 1 As shown, this proves that the product prepared is a chiral product.

[0071] Examples 13-18

[0072] This embodiment provides a series of methods for preparing chiral 1,4-diazaoctanes. The preparation methods and raw materials are the same as in Example 1. Compounds (Ib-a) are prepared using different side-arm bisoxazoline (SaBOX) ligands, temperatures, and times. The specific results are shown in Table 2.

[0073] Table 2 shows the effects of different types of SaBOX ligands, temperature, and time on yield and enantioselectivity in Examples 13-18.

[0074] Example Side arm bioxazoline ligand Temperature (°C) Time (h) Yield % Enantioselectivity % 13 L1 -20 12 43 73 14 L2 -20 12 48 82 15 L3 -20 12 55 76 16 L2 0 12 72 65 17 L2 -40 72 75 95 18 L2 -70 72 49 80

[0075] Example 19

[0076] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-b), which is a racemic product, and the steps are as follows:

[0077]

[0078] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3b (102 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain colorless oily product Ia-b (99 mg, yield: 80%).

[0079] This embodiment also provides a method for preparing chiral 1,4-diazaoctane (Ib-b), the steps of which are as follows:

[0080]

[0081] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3b (102 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-b (108 mg, yield: 87%; enantioselectivity: 96%).

[0082] The test data for product Ib-b are as follows: 1H NMR (500MHz, CDCl3): δ7.38 (dt, J=13.0, 7.3Hz, 4H), 7.31 (dd, J=8.2, 6.0Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 6. 88(d,J=8.7Hz,2H),6.81–6.72(m,6H),6.61(d,J=9.2Hz,2H),5.01(s,2H),4.65(d,J=11.1Hz,1H),4.38(d, J=15.5Hz,1H),3.92(dd,J=25.5,14.1Hz,2H),3.77(s,3H),3.73(s,6H),3.68(d,J=15.5Hz,1H),3.64–3.5 7(m,1H),3.50(s,3H),3.35(d,J=14.1Hz,1H),2.88(dd,J=15.3,12.7Hz,1H),2.67(dd,J=15.3,2.1Hz,1H); 13 C NMR (125MHz, CDCl3): δ172.2,170.9,157.7,153.3,151.3,144.8,142.8,137.1,134.2,128.7,128.1,127 .82,127.6,118.7,115.0,114.6,113.2,70.1,58.6,56.4,55.8,55.7,54.5,54.3,52.9,52.7,48.7,36.1.

[0083] The chiral product 1,4-diazaoctane (Ib-b) was analyzed by HPLC, and the results are as follows: Figure 2 As shown, this proves that the product prepared is a chiral product.

[0084] Example 20

[0085] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-c), which is a racemic product, and the steps are as follows:

[0086]

[0087] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3c (98 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ia-c (103 mg, yield: 84%).

[0088] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-c), the steps of which are as follows:

[0089]

[0090] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3c (98 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ib-c (92 mg, yield: 75%; enantioselectivity: >99%).

[0091] The test data for products Ib-c are as follows: 1 H NMR (500MHz, CDCl3): δ7.31(tt,J=7.6,2.3Hz,2H),7.11–7.05(m,3H),7.01–6.95(m,2 H),6.94–6.90(m,2H),6.82–6.73(m,6H),6.64–6.59(m,2H),4.68(d,J=11.4Hz,1H),4 .39(d,J=15.5Hz,1H),3.94(d,J=15.5Hz,2H),3.78(s,3H),3.77–3.69(m,7H),3.66–3 .58(m,1H),3.50(s,3H),3.36(d,J=14.1Hz,1H),2.98–2.88(m,1H),2.73–2.64(m,1H); 13 C NMR(125MHz, CDCl3):172.1,170.9,157.3,156.1,153.4,151.5,144.9,142.7,136.9,129.9,128.1,1 23.4,119.1,118.9,115.1,114.6,113.2,58.7,56.6,55.8,55.7,54.6,54.4,53.0,52.8,48.8,36.2.

[0092] The chiral product 1,4-diazaoctane (Ⅰb-c) was analyzed by HPLC, and the results are as follows: Figure 3 As shown, this proves that the product prepared is a chiral product.

[0093] Example 21

[0094] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-d), which is a racemic product, and the steps are as follows:

[0095]

[0096] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3d (97 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The mixture was reacted at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-d (99 mg, yield: 82%).

[0097] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-d), the steps of which are as follows:

[0098]

[0099] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3d (97 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-d (96 mg, yield: 79%; enantioselectivity: 99%).

[0100] The test data for products Ib-d are as follows: 1 H NMR (500MHz, CDCl3): δ7.02(d,J=8.7Hz,2H),6.84–6.73(m,8H),6.61(d,J=9.2Hz,2H),4.65(d,J= 12.2Hz,1H),4.38(d,J=15.5Hz,1H),4.00(t,J=6.3Hz,2H),3.92(dd,J=26.9,14.1Hz,2H),3.77(s ,3H),3.72(s,6H),3.71–3.65(m,1H),3.64–3.57(m,1H),3.53(t,J=6.2Hz,2H),3.50(s,3H),3.38 –3.33(m,4H),2.88(dd,J=15.3,12.7Hz,1H),2.67(dd,J=15.4,2.2Hz,1H),2.01(p,J=6.2Hz,2H); 13C NMR (125MHz, CDCl3): δ172.2,170.9,157.9,153.3,151.3,144.8,142.8,133.8,127.7,118.7,115.0,1 14.7,114.6,113.2,69.3,64.8,58.8,58.6,56.3,55.8,55.6,54.5,54.2,52.9,52.7,48.7,36.0,29.7.

[0101] The chiral product 1,4-diazaoctane (Ⅰb-d) was analyzed by HPLC, and the results are as follows: Figure 4 As shown, this proves that the product prepared is a chiral product.

[0102] Example 22

[0103] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-e), which is a racemic product, and the steps are as follows:

[0104]

[0105] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3e (95 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain colorless oily product Ia-e (82 mg, yield: 68%).

[0106] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ib-e), the steps of which are as follows:

[0107]

[0108] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40°C cryogenic reactor. Cyclopropane 3e (95 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-e (48 mg, yield: 40%; enantioselectivity: 98%).

[0109] The test data for products Ib-e are as follows: 1H NMR (500MHz, CDCl3): δ7.19–7.09(m,4H),6.85–6.71(m,6H),6.60(d,J=9.2Hz ,2H),4.71(d,J=11.0Hz,1H),4.39(d,J=15.5Hz,1H),3.92(dd,J=17.4,6.5Hz ,2H),3.78(s,3H),3.77–3.68(m,7H),3.65–3.58(m,1H),3.50(s,3H),3.35(d ,J=14.1Hz,1H),2.93(dd,J=15.3,12.7Hz,1H),2.67(dd,J=15.4,2.0Hz,1H); 13 CNMR (125MHz, CDCl3): δ171.9,170.8,153.5,151.6,148.1,144.9,142.4,141.0,128.2,121.3,120.6( q, J=255.4Hz)119.1,115.1,114.6,113.3,58.7,56.6,55.8,55.7,54.7,54.4,53.0,52.8,48.8,36.0.

[0110] The chiral product 1,4-diazaoctane (Ib-e) was analyzed by HPLC, and the results are as follows: Figure 5 As shown, this proves that the product prepared is a chiral product.

[0111] Example 23

[0112] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-f), which is a racemic product, and the steps are as follows:

[0113]

[0114] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3f (117 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ia-f (94 mg, yield: 70%).

[0115] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ib-f), the steps of which are as follows:

[0116]

[0117] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3f (117 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ib-f (112 mg, yield: 83%; enantioselectivity: 68%).

[0118] The test data for the obtained product Ib-f are as follows: 1 H NMR (500MHz, CDCl3): δ7.54 (d, J=2.2Hz, 1H), 6.99 (dd, J=8.5, 2.3Hz, 1H), 6.81–6.73 (m, 6H) ,6.69(d,J=8.5Hz,1H),6.59(d,J=9.2Hz,2H),4.62(d,J=11.5Hz,1H),4.37(d,J=15.4Hz,1H ),3.95–3.87(m,2H),3.82(s,3H),3.78(s,3H),3.76–3.68(m,7H),3.64–3.56(m,1H),3.50( s,3H),3.34(d,J=14.1Hz,1H),2.89(dd,J=15.4,12.5Hz,1H),2.61(dd,J=15.5,2.6Hz,1H); 13 C NMR (125MHz, CDCl3): δ172.0,170.8,157.1,153.4,151.5,144.8,142.5,137.8,136.3,127.8,119.0 ,115.1,114.6,113.3,110.9,86.5,58.6,56.5,56.1,55.8,55.7,54.6,54.4,53.0,52.7,48.7,36.1.

[0119] The chiral product 1,4-diazaoctane (Ⅰb-f) was analyzed by HPLC, and the results are as follows: Figure 6 As shown, this proves that the product prepared is a chiral product.

[0120] Example 24

[0121] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-g), the steps of which are as follows:

[0122]

[0123] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane (3 g, 88 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-g (91 mg, yield: 79%).

[0124] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-g), the steps of which are as follows:

[0125]

[0126] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40°C cryogenic reactor. Cyclopropane (3 g, 88 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-g (97 mg, yield: 84%; enantioselectivity: 80%).

[0127] The test data for product Ib-g are as follows: 1 H NMR (500MHz, CDCl3): δ6.82–6.72(m,7H),6.63(td,J=9.1,1.9Hz,4H),4.64(d,J=1 0.8Hz,1H),4.38(d,J=15.5Hz,1H),3.98–3.91(m,2H),3.83(s,3H),3.81–3.76(m, 6H),3.74(s,6H),3.72–3.67(m,1H),3.60(dd,J=15.3,9.7Hz,1H),3.51(s,3H),3. 35(d,J=14.1Hz,1H),2.91(dd,J=15.3,12.6Hz,1H),2.68(dd,J=15.4,2.3Hz,1H); 13C NMR (125MHz, CDCl3): δ172.2,171.0,153.4,151.4,149.2,148.0,144.9,142.8,134.6,118.9,118.6,115 .0,114.6,113.4,111.2,110.2,58.7,56.7,56.02,55.99,55.8,55.7,54.6,54.4,52.9,52.7,48.7,35.9.

[0128] The chiral product 1,4-diazaoctane (Ⅰb-g) was analyzed by HPLC, and the results are as follows: Figure 7 As shown, this proves that the product prepared is a chiral product.

[0129] Example 25

[0130] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-h), which is a racemic product, and the steps are as follows:

[0131]

[0132] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3h (83 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-h (93 mg, yield: 83%).

[0133] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-h), the steps of which are as follows:

[0134]

[0135] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40°C cryogenic reactor. Cyclopropane 3h (83 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-h (75 mg, yield: 67%; enantioselectivity: 96%).

[0136] The test data for product Ib-h are as follows: 1H NMR (500MHz, CDCl3): δ6.91(s,1H),6.84(d,J=8.0Hz,1H),6.81–6.66(m,7H),6.61(d,J=8.8Hz,2H),4.62(d,J=12.0Hz,1H),4.38(d,J=15.5Hz,1H),3 .99–3.90(m,2H),3.85–3.66(m,13H),3.65–3.57(m,1H),3.50(s,3H),3.35 (d,J=13.9Hz,1H),2.94–2.83(m,1H),2.66(d,J=15.0Hz,1H),2.17(s,3H); 13 C NMR (125MHz, CDCl3): δ172.2,171.0,156.7,153.3,151.3,144.8,142.9,133.4,129.1,126.9,124.8,11 8.7,115.0,114.6,113.1,109.9,58.7,56.4,55.8,55.7,55.4,54.5,54.3,52.9,52.7,48.8,36.2,16.6.

[0137] The chiral product 1,4-diazaoctane (Ⅰb-h) was analyzed by HPLC, and the results are as follows: Figure 8 As shown, this proves that the product prepared is a chiral product.

[0138] Example 26

[0139] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-i), which is a racemic product, and the steps are as follows:

[0140]

[0141] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3i (83 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ia-i (88 mg, yield: 83%).

[0142] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-i), the steps of which are as follows:

[0143]

[0144] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3i (83 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ib-i (101 mg, yield: 90%; enantioselectivity: 82%).

[0145] The test data for product Ib-i are as follows: 1 H NMR (500MHz, CDCl3): δ6.79–6.70(m,7H),6.62–6.55(m,4H),5.91(dd,J=7. 0,1.7Hz,2H),4.59(d,J=11.3Hz,1H),4.37(d,J=15.3Hz,1H),3.98–3.88(m, 2H),3.78(s,3H),3.76–6.68(m,7H),3.60(t,J=12.1Hz,1H),3.49(s,3H),3. 35(d,J=14.0Hz,1H),2.91(dd,J=15.5,12.4Hz,1H),2.62(d,J=14.6Hz,1H); 13 CNMR (125MHz, CDCl3): δ172.1,170.9,153.5,151.5,148.1,146.5,144.9,142.6,136.3,119.6,119.0, 115.1,114.6,113.3,108.5,107.3,101.1,58.7,57.0,55.8,55.7,54.6,54.5,53.0,52.7,48.8,36.4.

[0146] The chiral product 1,4-diazaoctane (Ⅰb-i) was analyzed by HPLC, and the results are as follows: Figure 9 As shown, this proves that the product prepared is a chiral product.

[0147] Example 27

[0148] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-j), which is a racemic product, and the steps are as follows:

[0149]

[0150] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3j (83 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-j (85 mg, yield: 74%).

[0151] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-j), the steps of which are as follows:

[0152]

[0153] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3j (88 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-j ​​(90 mg, yield: 78%; enantioselectivity: 84%).

[0154] The test data for product Ib-j ​​are as follows: 1 H NMR (500MHz, CDCl3): δ6.80–6.72(m,7H),6.60(ddd,J=14.2,7.6,2.1Hz,4H), 4.58(d,J=10.8Hz,1H),4.37(d,J=15.5Hz,1H),4.21(s,4H),3.93(t,J=14.3H z,2H),3.77(s,3H),3.76–3.68(m,7H),3.63–3.56(m,1H),3.48(s,3H),3.34( d,J=14.1Hz,1H),2.87(dd,J=15.4,12.6Hz,1H),2.63(dd,J=15.4,2.2Hz,1H); 13 C NMR (125MHz, CDCl3): δ172.1,170.9,153.3,151.4,144.8,143.6,142.7,142.4,135.6,119.7,118.8,11 7.5,115.5,115.0,114.6,113.2,64.5,64.4,58.6,56.5,55.8,55.7,54.5,54.3,52.9,52.7,48.8,36.2.

[0155] The chiral product 1,4-diazaoctane (Ⅰb-j) was analyzed by HPLC, and the results are as follows: Figure 10 As shown, this proves that the product prepared is a chiral product.

[0156] Example 28

[0157] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-k), the steps of which are as follows:

[0158]

[0159] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3k (82 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ia-k (100 mg, yield: 89%).

[0160] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ib-k), the steps of which are as follows:

[0161]

[0162] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L3 (38 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40 °C cryogenic reactor. Cyclopropane 3k (82 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40 °C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a colorless oily product Ib-k (94 mg, yield: 84%; enantioselectivity: 95%).

[0163] The test data for the obtained product Ib-k are as follows: 1H NMR (500MHz, CDCl3): δ7.43(t,J=8.7Hz,2H),7.22(td,J=8.3,7.8,1.3Hz,1H),7.17(td, J=7.5,0.9Hz,1H),6.85–6.80(m,2H),6.80–6.70(m,6H),6.35(s,1H),4.86(dd,J=11.4, 4.2Hz,1H),4.41(d,J=15.6Hz,1H),4.04(d,J=15.6Hz,1H),3.90(ddd,J=15.1,10.6,1.9 Hz,1H),3.81–3.70(m,9H),3.66–3.52(m,5H),3.41(d,J=13.9Hz,1H),2.94–2.81(m,2H); 13 C NMR (125MHz, CDCl3): δ172.2,170.7,157.3,155.0,153.3,152.0,144.6,142.6,128.3,123.9,122.8,120 .1,118.5,115.0,114.7,113.9,111.3,103.7,58.1,55.8,55.7,54.8,54.6,53.1,52.8,52.7,48.8,32.8.

[0164] The chiral product 1,4-diazaoctane (Ib-k) was analyzed by HPLC, and the results are as follows: Figure 11 As shown, this proves that the product prepared is a chiral product.

[0165] Example 29

[0166] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-l), the steps of which are as follows:

[0167]

[0168] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3L (83 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ia-l (107 mg, yield: 93%).

[0169] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ib-l), the steps of which are as follows:

[0170]

[0171] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L1 (35 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40°C cryogenic reactor. Cyclopropane 3L (87 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ib-l (102 mg, yield: 89%; enantioselectivity: 92%).

[0172] The test data for product Ib-l are as follows: δ 7.71 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.32–7.23 (m, 2H), 7.05 (s, 1H), 6.87–6.82 (m, 2H), 6.78–6.71 (m, 6H), 5.06 (dd, J = 12.3, 3.2 Hz, 1H), 4. 40(d,J=15.6Hz,1H),4.00(d,J=15.7Hz,1H),3.80–3.71(m,10H),3.62–3.54(m,5H), 3.37(d,J=14.0Hz,1H), 2.97(dd,J=15.1,12.3Hz,1H), 2.84(dd,J=15.1,3.3Hz,1H); 13 C NMR (125MHz, CDCl3): δ172.1,170.7,153.3,151.9,147.2,144.6,142.0,139.7,139.4,124.4,124.2,1 23.4,122.3,121.1,118.4,115.2,114.7,113.6,58.3,55.8,55.7,54.7,54.0,53.0,52.9,48.2,35.3.

[0173] The chiral product 1,4-diazaoctane (Ib-l) was analyzed by HPLC, and the results are as follows: Figure 12 As shown, this proves that the product prepared is a chiral product.

[0174] Example 30

[0175] This embodiment provides a method for preparing 1,4-diazaoctane (Ⅰa-m), the steps of which are as follows:

[0176]

[0177] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol), cyclopropane 3m (78 mg, 0.3 mmol), and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (2.0 mL). The reaction was carried out at room temperature for 12 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ia-m (84 mg, yield: 77%).

[0178] Furthermore, this embodiment provides a method for preparing chiral 1,4-diazaoctane (Ⅰb-m), the steps of which are as follows:

[0179]

[0180] In a reaction flask, copper trifluoromethanesulfonate (14 mg, 0.04 mmol) and L2 (39 mg, 0.048 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at room temperature for 30 minutes. The mixture was then transferred to a -40°C cryogenic reactor. Cyclopropane 3m (78 mg, 0.3 mmol) and imidazoline compound 2a (56 mg, 0.2 mmol) were dissolved in dichloromethane (1.0 mL) and slowly added dropwise to the reaction system. The mixture was stirred at -40°C for 72 hours. After removing the solvent, the crude product was separated by silica gel column chromatography to obtain a white solid product Ib-m (96 mg, yield: 88%; enantioselectivity: 75%).

[0181] The test data for the obtained product Ib-m are as follows: 1 H NMR (500MHz, CDCl3): δ7.34–7.27(m,4H),7.23–7.17(m,1H),6.86–6.80(m,2H),6.79–6.6 9(m,6H),6.29(dd,J=16.2,1.8Hz,1H),6.12(dd,J=16.1,4.0Hz,1H),4.36(d,J=15.6Hz,1H ),4.29(d,J=12.6Hz,1H),4.01(d,J=15.6Hz,1H),3.79–3.70(m,10H),3.61–3.50(m,5H), 3.39(dd,J=13.8,2.7Hz,1H), 2.67(dd,J=15.1,12.6Hz,1H), 2.45(dd,J=15.1,3.0Hz,1H); 13C NMR (125MHz, CDCl3): δ172.5,170.9,153.2,151.5,144.6,143.1,136.8,130.6,128.7,128.6,127 .6,126.5,118.2,115.1,114.7,113.4,58.3,55.9,55.7,54.7,54.5,54.4,52.9,52.8,48.2,34.1.

[0182] The chiral product 1,4-diazaoctane (Ⅰb-m) was analyzed by HPLC, and the results are as follows: Figure 13 As shown, this proves that the product prepared is a chiral product.

[0183] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing 1,4-diazaoctane, characterized in that, Includes the following steps: The imidazoline compound with the structure shown in Formula II was reacted with the cyclopropane compound with the structure shown in Formula III in the presence of a Lewis acid catalyst and an organic solvent to obtain the compound with the structure shown in Formula Ia: ； R1 is selected from unsubstituted or C-substituted varieties. 1~6 alkyl, C 1~6 alkoxy groups, C1~6 Halogenated alkyl, halogen, nitro-substituted aryl, unsubstituted or C-substituted 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl groups, halogens, nitro-substituted heteroaryl groups, unsubstituted or C-substituted groups 1~6 alkyl, phenyl substituted C 2-10 alkenyl, unsubstituted or C 1~6 alkyl, phenyl substituted C 2-10 The alkynyl group, unsubstituted or halogenated, nitro, phenyl-substituted C 1~6 Alkyl groups; R2 is selected from C 2~10 The ester group and nitrile group; R3 is selected from unsubstituted or C-substituted products. 1~6 Alkyl, halogen, nitro, trifluoromethyl, C 1~6 alkoxy-substituted phenyl; The Lewis acid catalyst is selected from a trifluoromethanesulfonate metal salt; the trifluoromethanesulfonate metal salt is selected from copper trifluoromethanesulfonate. The organic solvent is selected from at least one of dichloromethane, trichloromethane, toluene, tetrahydrofuran, or dichloroethane; The raw materials used in the preparation method further include a sidearm bisoxazoline ligand; the sidearm bisoxazoline ligand is selected from one of the following structural formulas: 。 2. The method for preparing 1,4-diazaoctane according to claim 1, characterized in that, The molar ratio of the imidazoline compound with the structure shown in Formula II, the cyclopropane compound with the structure shown in Formula III, and the Lewis acid catalyst is 1:(1~5):(0.1~0.2).

3. The method for preparing 1,4-diazaoctane according to claim 1, characterized in that, The molar ratio of the imidazoline compound with the structure shown in Formula II, the cyclopropane compound with the structure shown in Formula III, the Lewis acid catalyst, and the sidearm bisoxazoline ligand is 1:(1~5):(0.1~0.2):(0.12~0.24).

4. The method for preparing 1,4-diazaoctane according to claim 1, characterized in that, The reaction temperature is -70℃ to 60℃.

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