Process for preparing ring-expanded or chain-extended amines from saturated amines

Abstract

The invention discloses a method for preparing ring-expanded amine or chain-extended amine from saturated amine, which comprises the following steps: in a glove box filled with nitrogen or inert gas, adding saturated amine, a first solvent, alkyne and a first catalyst into a first reaction container, heating and stirring, and carrying out ring expansion reaction to obtain ring-expanded amine or chain-extended amine; when two ends of alkyne are respectively connected with CO2Me and H, the method further comprises the following steps: adding the obtained ring-extended amine or chain-extended amine, a second solvent and alkali into a second reaction container, and heating and stirring to fully hydrolyze the ring-extended amine or chain-extended amine to obtain corresponding carboxylic acid; and at room temperature, adding the obtained carboxylic acid, a third solvent and a second catalyst into a third reaction container, then putting the third reaction container into a high-pressure kettle, filling hydrogen, and carrying out a stirring reaction to obtain completely reduced amine. The method does not use a transition metal catalyst, is good in chemical selectivity, wide in substrate application range and wide in functional group compatibility, and can be used for later functional group modification of drug molecules.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and specifically to a method for preparing ring-extended amines or chain-extended amines from saturated amines. Background Technology

[0002] Amines, as an important class of compounds, play a crucial role in medicine, pesticides, materials, and catalysts. They also possess significant biological activities; for example, proteins and alkaloids are derivatives of amines, and many clinically used drugs are amines and their derivatives. Cyclic amines, a very important class of amines, have ring sizes that greatly influence their physicochemical properties and spatial conformation, and can alter their biological activity by affecting their binding to receptors. Therefore, controlling the ring size of cyclic amines through chemical synthesis is of great significance to medicinal chemistry research.

[0003] Current research indicates that many medium-ring (8-11 membered ring) nitrogen-containing compounds possess excellent biological activity and potential medicinal value, attracting widespread attention from medicinal chemists. However, due to thermodynamic and kinetic mismatches, coupled with the unique transcyclic interactions inherent in medium-ring compounds, more stable small-ring byproducts are frequently generated during reactions. Therefore, the synthesis of medium-ring compounds has always been one of the challenges in organic synthesis, limiting their applications. Thus, developing efficient and universal methods for constructing medium-ring nitrogen-containing compounds is of great significance.

[0004] One important route for synthesizing medium-ring nitrogen-containing heterocyclic compounds is through cycloaddition reactions of unsaturated precursors. This method is usually based on the presence of unsaturated functional groups in the substrate, and the medium-ring nitrogen-containing heterocycle is constructed through cycloaddition reactions (KRLee, S. Ahn, S. Lee. Org. Lett. 2021, 23, 3735; Y. Liu, Y. He, Y. Liu, K. Wei, W. Guo. Org. Chem. Front. 2021, 8, 7004; A. Wu, Q. Feng, HHY Sung, I. D. Williams, J. Sun. Angew. Chem. Int. Ed. 2019, 58, 6776; (L.-C.Yang, Z.-Q.Rong, Y.-N.Wang, ZYTan, M.Wang, Y.Zhao. Angew.Chem.Int.Ed. 2017, 56, 2927; Y.-N.Wang, L.-C.Yang, Z.-Q.Rong, T.-L.Liu, R.Liu, Y.Zhao.Angew.Chem.Int.Ed. 2018, 57, 1596; H.Uno, N.Punna, E.Tokunaga, M.Shiro, N.Shibata.Angew.Chem.Int.Ed. 2020, 59, 8187). Although these methods can synthesize a variety of nitrogen-containing medium-ring compounds, they are all based on the presence of unsaturated functional groups in the substrate, making them difficult to apply to the later functionalization of drugs. Reports on ring-expansion reactions of nitrogen-containing saturated heterocycles are still scarce.

[0005] Sun Jianwei's research group reported that N-Ts (p-toluenesulfonyl) protected 5 / 6-membered cyclic azahexaacetal substrates can undergo ring-expansion reactions with silanoxyalkynes under Lewis acid catalysis to give 7 / 8-membered α-β unsaturated lactam products (W. Zhao, H. Qian, Z. Li, J. Sun. Angew. Chem. Int. Ed. 2015, 54, 10005):

[0006]

[0007] Chen Yifeng's research group developed a ruthenium-catalyzed formal [5+2] reaction using 5 / 6-membered saturated cyclic amines as substrates and glycine derivatives as two-carbon synthons to obtain α,β-unsaturated lactam ring-expansion products. Subsequent functionalization of the products yielded α-ketoamides, saturated amides, and cyclic amine derivatives (L.Wu, H.Xia, J.Bai, Y.Xi, X.Wu, L.Gao, J.Qu, Y.Chen. Nature Chemistry 2024, 16, 1951).

[0008]

[0009] However, both of the above methods involve breaking the carbon-nitrogen bond for insertion, and can only be applied to the ring expansion of 5 / 6-membered saturated cyclic amines. They are difficult to implement for other types of saturated amine substrates or for insertion at other sites. Therefore, developing efficient and universal novel ring expansion strategies for the synthesis of medium-ring nitrogen-containing heterocyclic compounds remains of great significance. Summary of the Invention

[0010] The purpose of this invention is to provide an efficient, universal, and convenient method for synthesizing medium-ring nitrogen-containing heterocyclic compounds. This method breaks the limitation that carbon-carbon bonds can only be inserted into the carbon-nitrogen bonds of saturated cyclic amines, providing more options for the post-modification of related drugs.

[0011] Therefore, the present invention adopts the following technical solution:

[0012] A method for preparing ring-extended amines or chain-elongated amines from saturated amines includes the following steps:

[0013] In a glove box filled with nitrogen or inert gas, a saturated amine, a first solvent, an alkyne, and a first catalyst are added to the first reaction vessel. The mixture is stirred at 100-160°C to allow for a complete ring-expansion reaction, yielding a ring-expanded amine or a chain-extended amine, wherein:

[0014] The saturated amine has the following structure:

[0015]

[0016] The structural formula of the alkyne is:

[0017] The first catalyst is triarylborane, and its molar ratio with the saturated amine is (10-20):100.

[0018] In the above structural formula, n is 0 to 10; X is 0 or S;

[0019] The structural formula of the triarylborane is B(R) 11 )3, where R 11 It is a phenyl, pentafluorophenyl, 3,5-di(trifluoromethyl)-substituted phenyl or 2,4,6-trifluoro-substituted phenyl;

[0020] The reaction formula for the ring expansion reaction is as follows:

[0021]

[0022] in:

[0023] R 1 It is alkyl, aryl, or substituted aryl;

[0024] R2 and R 3 They are independently selected from hydrogen, alkyl, amino, ether, ester, aryl, substituted aryl, and heteroaryl groups, and all substituted aryl groups are applicable;

[0025] R 4 It can be hydrogen, alkyl, amino, ester, aryl, substituted aryl or heteroaryl, and all substituted aryl groups are applicable;

[0026] R 5 R 6 R 7 Each is independently selected from alkyl, aryl, and substituted aryl groups;

[0027] R 8 It can be alkyl, aryl, substituted aryl or heteroaryl, and all substituted aryl groups are applicable;

[0028] R 9 and R 10 They are independently selected from hydrogen, alkyl, ester, cyano, carbonyl, aldehyde, trifluoromethyl, sulfonyl, aryl, substituted aryl, and heteroaryl groups, and all substituted aryl groups are applicable;

[0029] The first solvent is tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or an aromatic solvent, and the amount of the first solvent is sufficient to dissolve all the raw materials;

[0030] When with R 1 R 5 R 6 or R 7 When the amine is alkyl, trimethyl trifluoromethanesulfonate is added as an additive, and the molar ratio of trimethyl trifluoromethanesulfonate to the saturated amine is 5:100.

[0031] When R 9 For CO2Me, R 10 When hydrogen is used, 2,6-dimethylpyridine is added as an additive, and the molar ratio of 2,6-dimethylpyridine to the saturated amine is 10:100.

[0032] Preferably, the equivalence ratio of the alkyne to the saturated amine is (1.5–2):1. Preferably, the ring expansion reaction takes 12–24 hours.

[0033] When R 9 For CO2Me, R 10 When the hydrogen is used, the above method further includes the following steps:

[0034] Hydrolysis reaction: The obtained ring-expanding amine or chain-extending amine, along with a second solvent and a base, are added to the second reaction vessel. The mixture is stirred at 100–110 °C to allow for complete hydrolysis, yielding the corresponding carboxylic acid. The reaction formula is as follows:

[0035]

[0036] Reduction reaction: At room temperature, the carboxylic acid obtained from the hydrolysis reaction, the third solvent, and the second catalyst are added to the third reaction vessel. Then, the third reaction vessel is placed in an autoclave, hydrogen gas is introduced, and the mixture is stirred to allow the reaction to proceed fully, yielding a completely reduced amine. The reaction equation is as follows:

[0037]

[0038] In the above hydrolysis reaction:

[0039] The base is NaOH, LiOH or KOH, and the equivalent ratio of the base to the substrate of the hydrolysis reaction is 6 to 12 equivalents;

[0040] The second solvent is a mixture of water and methanol, with a volume ratio of 1:3.

[0041] Hydrolysis time is 2–12 hours;

[0042] In the reduction reaction described above:

[0043] The second catalyst is palladium on carbon (wet palladium on carbon), and the equivalence ratio of palladium on carbon (wet palladium on carbon) to the substrate of the reduction reaction is 10% to 30%.

[0044] The third solvent is a mixture of dichloromethane and ethanol, with a volume ratio of 1:1; the hydrogen gas pressure is 20-50 MPa.

[0045] The reduction reaction time is 24 to 48 hours.

[0046] The preferred option is:

[0047] When R 1 When the aryl group is substituted, the substituted aryl group is 2,4,6-trimethylphenyl or 2,6-dimethyl-4-methoxyphenyl;

[0048] When R 5 R 6 Or R 7 When the aryl group is substituted, the substituted aryl group is 2,4,6-trimethylphenyl or 2,6-dimethyl-4-methoxyphenyl;

[0049] When R 2 When the heteroaryl group is a furanyl or thiophene group;

[0050] When R 3 When the heteroaryl group is a furanyl, thiophene, or pyridinyl group;

[0051] When R 4When the heteroaryl group is a furanyl, thiophene, or pyridinyl group;

[0052] When R 8 When the heteroaryl group is a furanyl, thiophene, or pyridinyl group;

[0053] When R 9 When the heteroaryl group is a furanyl, thiophene, pyridinyl, or pyrimidinyl group;

[0054] When the R 10 When the heteroaryl group is a furanyl, thiophene, pyridinyl, or pyrimidinyl group, the heteroaryl group is used.

[0055] This invention modifies the skeleton of saturated amine compounds using a boron catalyst, employing alkynes as two-carbon synthons to achieve carbon-carbon bond insertion. The tertiary amine substrates used in this invention yield the corresponding enamines under the catalysis of boron Lewis acids. The enamines then undergo a 2+2 cycloaddition reaction with a series of alkynes to give a cyclobutene intermediate. This intermediate further undergoes a reverse electrocyclization reaction to open the ring, yielding a series of medium-ring nitrogen-containing heterocyclic compounds. This invention is also applicable to chain-like tertiary amines and drug molecules containing tertiary amine structures.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] 1. This invention does not require the use of relatively expensive metal reagents, but instead uses boron Lewis acid as a catalyst, which is beneficial to environmental protection, reduces production costs, and is easy to scale up for production;

[0058] 2. In this invention, the two-carbon structure insertion only occurs at the C(α)-C(β) meta position, exhibiting good chemoselectivity and regioselectivity, and this selectivity is difficult to achieve by other methods;

[0059] 3. The present invention has a broad substrate scope, reacting well not only with saturated cyclic amines of various substitutions and ring sizes, but also with chain amines. It exhibits high reactivity with both cyclic and chain tertiary amines containing substituents at different positions, and is compatible with alkynes containing different substituents. Furthermore, it has good applicability to late-stage functionalization modifications of drug molecules containing tertiary amine structures, and can be applied to drug research and development and production.

[0060] 4. The reaction product of the present invention is subjected to late-stage functionalization and converted into its saturated derivative through continuous hydrolysis and hydrogenation reduction reactions to obtain the continuously ring-expanded product;

[0061] 5. The functional groups in this invention have strong compatibility, do not require pre-functionalization, are easy to scale up for production, and are compatible with various alkyl, halogen, amino, ether, ester, aryl, substituted aryl or heteroaryl substituents;

[0062] 6. This invention can be scaled up to the gram level, and further scaled up can be used for large-scale production. Detailed Implementation

[0063] The method of the present invention will be described in detail below with reference to embodiments. These embodiments are only for understanding the present invention and are not intended to limit the scope of the invention.

[0064] In the following examples and reaction formulas:

[0065] LA stands for catalyst;

[0066] TMSOTf is trimethylsilyl trifluoromethanesulfonate;

[0067] 2,6-Lutidine is 2,6-dimethylpyridine;

[0068] Pd / C is wet palladium on carbon;

[0069] 1,4-dioxane is 1,4-dioxane;

[0070] DCM stands for dichloromethane.

[0071] Example 1

[0072] A method for preparing dimethyl(2E,4E)-1-ethyl-1,6,7,8-tetrahydroazacyclooctyl-3,4-dicarboxylic acid ester includes the following steps:

[0073] In a nitrogen-filled glove box, 22.6 mg (0.2 mmol, 1.0 equiv) of 1-ethylpiperidine (1a), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst, 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 100 °C for 12 hours to obtain dimethyl (2E,4E)-1-ethyl-1,6,7,8-tetrahydroazacyclooctyl-3,4-dicarboxylic acid ester (3a), as shown in the following reaction formula:

[0074]

[0075] The catalyst is B(2,4,6-F3C6H2)3, with the following structural formula:

[0076]

[0077] After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3a, which was a colorless oil with a yield of 50%.1 H NMR(400MHz, CDCl3)δ7.55(s,1H),6.29(dd,J=9.9,7.1Hz,1H),4.00–3.90(m,1H),3.73(s,3H),3.60(s,3H),3.23–3.0 8(m,2H),2.83(dd,J=15.0,3.4Hz,1H),2.50–2.40(m,2H),1.77–1.66(m,1H),1.20(t,J=7.2Hz,3H),1.16–1.12(m,1H). 13 C NMR(101MHz, CDCl3)δ169.7,169.6,150.2 134.5,133.9,91.9,52.8,52.0,51.2,44.6,25.2,17.7,14.5.HRMS(ESI)calcd.for C 13 H 19 NNaO4 + (M+Na) + :276.1206,Found:276.1202.

[0078] Example 2

[0079] A method for preparing trimethyl(2E,4E)-1-benzyl-1,6,7,8-tetrahydroazacyclooctyl-3,4,6-tricarboxylic acid ester includes the following steps:

[0080] In a nitrogen-filled glove box, 46.7 mg (0.2 mmol, 1.0 equiv) of methyl 1-benzylpiperidine-4-carboxylate (1b), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst, 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to give trimethyl(2E,4E)-1-benzyl-1,6,7,8-tetrahydroazacyclooctyl-3,4,6-tricarboxylate (3b), as shown in the following reaction formula:

[0081]

[0082] The catalyst used is the same as in Example 1, namely B(2,4,6-F3C6H2)3.

[0083] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3b, which was a light yellow solid with a yield of 66%. 1H NMR (400MHz, CDCl3) δ7.70(s,1H),7.37–7.28(m,3H),7.24–7.21(m,2H),6.33(d,J=9.5Hz,1H),4.33(d,J=15.1Hz,1H),4.25(d,J=15.1Hz,1H),3 .81–3.77(m,1H),3.73(s,3H),3.66(s,3H),3.61(s,3H),3.57–3.49(m, 1H), 2.84 (dd, J=14.8, 4.4Hz, 1H), 1.76–1.64 (m, 1H), 1.28–1.12 (m, 1H). 13 C NMR(101MHz, CDCl3)δ173.2,169.3,168.7,150.6,135.7,133.6,132.2,129.0,128.4,127.9,93.0,61.9,52.2,51.4,44.3,43.0,21.2.HRMS(ESI)calcd.for C 20 H 23 NNaO6 + (M+Na) + :396.1418,Found:396.1411.

[0084] Example 3

[0085] A method for preparing dimethyl(2E,4E)-1-benzyl-1,6,6a,7,8,9,10,10a-octahydrobenzo[b]azacyclooctyl-3,4-dicarboxylic acid ester, comprising the following steps:

[0086] In an argon-filled glove box, 45.9 mg (0.2 mmol, 1.0 equiv) of 1-benzyldecahydroquinoline (1c), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl (2E,4E)-1-benzyl-1,6,6a,7,8,9,10,10a-octahydrobenzo[b]azacyclooctyl-3,4-dicarboxylic acid ester (3c). The reaction formula is as follows:

[0087]

[0088] The catalyst LA was the same as in Example 1, namely B(2,4,6-F3C6H2)3;

[0089] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3c, which was a light yellow oil with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ7.66(s,1H),7.33–7.16(m,5H),6.36(t,J=7.5Hz,1H),4.35(d,J=15.7Hz,1H),4.23(d,J=15.7Hz,1H),3.68(s, 3H),3.57(s,3H),2.48–2.39(m,1H),1.94–1.89(m,1H),1.75–1.62(m,2H),1.58–1.43(m,3H),1.20–1.14(m,1H),1.05–0.81(m,4H). 13 C NMR (101MHz, CDCl3) δ170.1,169.4,151.8,137.6,133.9,133.6,128.8,127.9,127.6, 93.3,58.3,55.7,52.0,51.4,32.9,31.8,31.7,30.5,25.7,25.4.HRMS(ESI)calcd.for C 22 H 28 NO4 + (M+H) + :370.2013,Found:370.2011.

[0090] Example 4

[0091] A method for preparing dimethyl(5E,7E)-4-benzyl-3,4-dihydro-2H-1,4-thiazacyclooctyl-6,7-dicarboxylic acid ester includes the following steps:

[0092] In a nitrogen-filled glove box, 38.7 mg (0.2 mmol, 1.0 equiv) of 4-benzylthiomorpholine (1d), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl (5E,7E)-4-benzyl-3,4-dihydro-2H-1,4-thiazazepine-6,7-dicarboxylic acid ester (3d). The reaction formula is as follows:

[0093]

[0094] The catalyst LA was the same as in Example 1, namely B(2,4,6-F3C6H2)3;

[0095] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3d, which was a yellow oil with a yield of 45%. 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.40–7.29(m,5H),6.63(s,1H),4.41(d,J=15.1Hz,1H),4.33(d,J=15.1Hz ,1H),3.91–3.81(m,1H),3.78(s,3H),3.65(s,3H),3.11–3.06(m,1H),2.23–2.16(m,1H),2.06–2.00(m,1H). 13 C NMR(101MHz, CDCl3)δ169.1,168.0,152.2,146.8,135.3,129.0,128.5,128.1,121.9,93.0,61.7,52.4,51.5,43.9,19.4.HRMS(ESI)calcd.for C 17 H 19 NNaO4S + (M+Na) + :356.0927,Found:356.0921.

[0096] Example 5

[0097] A method for preparing dimethyl(2E,4E)-1-benzyl-1,6,7,8,9,10-hexahydroazacyclodec-3,4-dicarboxylic acid ester comprises the following steps:

[0098] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-benzylazacyclooctane (1e), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to give dimethyl (2E,4E)-1-benzyl-1,6,7,8,9,10-hexahydroazacyclodec-3,4-dicarboxylic acid ester (3e). The reaction formula is as follows:

[0099]

[0100] The catalyst LA was the same as in Example 1, namely B(2,4,6-F3C6H2)3;

[0101] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3e, which was a light yellow solid with a yield of 73%. 1 H NMR(400MHz, CDCl3)δ7.77(s,1H),7.36–7.27(m,3H),7.25–7.20(m,2H),6. 80(dd,J=12.0,5.1Hz,1H),4.35(d,J=15.4Hz,1H),4.23(d,J=15.4Hz,1H), 3.89–3.81(m,1H),3.71(s,3H),3.61(s,3H),2.72(dd,J=14.7,4.3Hz,1H), 2.40–2.32(m,1H),2.09–1.98(m,2H),1.80–1.67(m,2H),1.23–1.11(m,3H). 13 C NMR (101MHz, CDCl3) δ170.2,168.6,149.5,145.0,136.3,128.9,128.9,128.0,1 27.7,90.8,58.4,52.0,51.2,44.0,31.2,28.5,26.0,25.5.HRMS(ESI)calcd.for C 20 H 26 NO4 + (M+H) + :344.1856,Found:344.1852.

[0102] Example 6

[0103] A method for preparing dimethyl(2E,4E)-1-benzylazine pentadecano-2,4-diene-3,4-dicarboxylic acid ester includes the following steps:

[0104] In a nitrogen-filled glove box, 54.7 mg (0.2 mmol, 1.0 equiv) of 1-benzylazacyclotridecane (1f), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl (2E,4E)-1-benzylazacyclopentadecano-2,4-diene-3,4-dicarboxylic acid ester (3f), as shown in the following reaction formula:

[0105]

[0106] The catalyst LA was the same as in Example 1, namely B(2,4,6-F3C6H2)3;

[0107] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3f, which was a light yellow solid with a yield of 53%. 1 H NMR(400MHz, CDCl3)7.64(s,1H),7.24–7.05(m,5H),6.93(dd,J=9.6,4.5Hz,1H),4.88(d,J=15.4Hz,1H),3 .88(d,J=15.4Hz,1H),3.57(s,3H),3.29(s,3H),2.31–2.17(m,1H),1.98–1.88(m,1H),1.61–1.11(m,18H). 13 C NMR (101MHz, CDCl3) δ170.1,167.8,148.7,147.0,136.7,128.5,128.1,127.3,127.2, 91.7,51.5,51.2,28.7,28.1,27.6,25.6,25.3,24.5,24.3,23.5.HRMS(ESI)calcd.for C 25 H 35 NNaO4 + (M+Na) + :436.2458,Found:436.2462.

[0108] Example 7

[0109] A method for preparing dimethyl(E)-2-((E)-benzyl)-3-(dibenzylamino)methylene)succinate includes the following steps:

[0110] In a nitrogen-filled glove box, 60.3 mg (0.2 mmol, 1.0 equiv) of N,N-dibenzyl-2-phenylethyl-1-amine (1 g), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to obtain dimethyl(E)-2-((E)-benzylene)-3-(dibenzylamino)methylene)succinate (3 g). The reaction formula is as follows:

[0111]

[0112] The catalyst LA is B(C6F5)3, with the following structural formula:

[0113]

[0114] After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain 3g of product, which was a yellow oil with a yield of 61%. 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.77(s,1H),7.65–7.59(m,2H),7.42–7.34(m,3H),7.30–7.24(m ,6H),7.02–6.97(m,4H),4.51(d,J=15.7Hz,2H),4.13(d,J=15.7Hz,2H),3.69(s,3H),3.60(s,3H). 13 C NMR (101MHz, CDCl3) δ170.2,168.5,149.3,141.3,136.3,135.4,130.4,129.3,128.6,127.6,127.3,126.6,92.6,52.1,51.5.HRMS(ESI)calcd.for C 28 H 28 NO4 + (M+H) + :442.2013,Found:442.2017.

[0115] Example 8

[0116] A method for preparing dimethyl(2E,3E)-2-(5,5-dimethylhex-3-yn-1-ylidene)-3-((methyl(naphthyl-1-ylmethyl)amino)methylene)succinate, comprising the following steps:

[0117] In a nitrogen-filled glove box, 58.3 mg (0.2 mmol, 1.0 equiv) of terbinafine (1 h), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 h to give dimethyl(2E,3E)-2-(5,5-dimethylhex-3-yn-1-ylidene)-3-((methyl(naphthyl-1-ylmethyl)amino)methylene)succinate (3 h). The reaction formula is as follows:

[0118]

[0119] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0120] After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3h, which was a colorless oil with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.89(s,1H),7.87(s,1H),7.83–7.80(m,2H),7.58–7.50(m,2H),7.48–7.43(m,1H),7.36(d,J=7.6Hz,1H),6.83(t, J=7.2Hz,1H),4.92(d,J=15.4Hz,1H),4.75(d,J=15.4Hz,1H),3.68(s,3H),3.63(s,3H),2.92(d,J=7.6Hz,2H),2.83(s,3H),1.12(s,9H). 13 C NMR (101MHz, CDCl3) δ169.4,168.1,150.3,140.4,133.9,131.5,131.2,129.4,129.0,128.8,126.7 ,126.1,125.9,125.4,122.8,91.5,90.0,74.1,52.1,51.3,31.2,27.3,20.0.HRMS(ESI)calcd.for C 27 H 31 NNaO4 + (M+Na) + :456.2145,Found:456.2143.

[0121] Example 9

[0122] A method for preparing dimethyl(2E,4E,6Z)-1-benzyl-6-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1,6,7,8-azacyclooctyl-3,4-dicarboxylic acid ester, comprising the following steps:

[0123] In a nitrogen-filled glove box, 80.0 mg (0.2 mmol, 1.0 equiv) of N-benzyl loratadine (1i), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl (2E,4E,6Z)-1-benzyl-6-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1,6,7,8-azacyclooctyl-3,4-dicarboxylic acid ester (3i), as shown in the following reaction formula:

[0124]

[0125] The catalyst LA was the same as in Example 1, namely B(2,4,6-F3C6H2)3;

[0126] After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3i, which was a yellow oil with a yield of 30%. 1 H NMR(400MHz, CDCl3)δ8.00(d,J=6.9Hz,1H),7.58(s,1H),7.19(s,1H),7.14–7.0 7(m,2H),7.05–6.96(m,3H),6.93–6.80(m,2H),6.51–6.42(m,2H),6.15(s,1H), 4.24(d,J=15.0Hz,1H),4.15(d,J=15.0Hz,1H),3.97–3.87(m,1H),3.80(s,3H), 3.77(s,3H),3.31(dd,J=15.6,6.4Hz,1H),3.15–3.04(m,3H),2.99–2.76(m,3H). 13C NMR (101MHz, CDCl3) δ174.5,170.4,153.0,143.1,136.3,133.7,133.0,130.5,129.5,128.7,128.5,127.8,127.4,125. 4,120.9,120.9,120.0,115.7,112.2,110.2,94.1,61.5,53.0,51.8,49.3,39.3,35.7,35.1,28.4.HRMS(ESI)calcd.for C 32 H 30 ClN2O4 + (M+H) + :541.1889,Found:541.1884.

[0127] Example 10

[0128] A method for preparing (2E,4Z)-1-metrimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooctyl-3-onitrile comprises the following steps:

[0129] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 50.9 mg (0.4 mmol, 2.0 equiv) of 3-phenylpropynitrile (2b), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA) and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 150 °C for 24 hours to obtain (2E,4Z)-1-trimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooctyl-3-onitrile (3j). The reaction formula is as follows:

[0130]

[0131] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0132] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3j, which was a white solid with a yield of 50%. 1H NMR (400MHz, CDCl3) δ7.57–7.51(m,2H),7.44–7.36(m,2H),7.34–7.30(m,1H),6.93(s,2H),6.78(s,1H),5.65(t,J=8.3Hz,1H),4.5 7–4.42(m,1H),3.18–2.94(m,2H),2.68–2.56(m,1H),2.40(s,3H),2.30(s,3H),2.23(s,3H),1.90–1.79(m,1H),1.26–1.18(m,1H). 13 C NMR (101MHz, CDCl3) δ151.5,144.0,140.5,138.2,137.9,130.0,129.8,128.5, 127.8,127.4,126.1,123.4,78.3,49.0,26.1,20.9,18.8.HRMS(ESI)calcd.for C 23 H 25 N2 + (M+H) + :329.2012,Found:329.2010.

[0133] Example 11

[0134] A method for preparing ((2E,4Z)-1-trimethylphenyl-4-(pyrimidin-5-yl)-1,6,7,8-tetrahydroazacyclooct-3-yl)(4-methoxyphenyl) ketone, comprising the following steps:

[0135] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 95.3 mg (0.4 mmol, 2.0 equiv) of 1-(4-methoxyphenyl)-3-(pyrimidin-5-yl)prop-2-yn-1-one (2c), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA) and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to obtain ((2E,4Z)-1-trimethylphenyl-4-(pyrimidin-5-yl)-1,6,7,8-tetrahydroazacyclooct-3-yl)(4-methoxyphenyl) methyl ketone (3k), as shown in the following reaction formula:

[0136]

[0137] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0138] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3K, which was a brown foamy solid with a yield of 45%. 1 H NMR (400MHz, CDCl3) δ8.94 (s, 1H), 8.69 (s, 2H), 7.38 (d, J = 8.7Hz, 2H), 7.34 (s, 1H) ,6.94(s,1H),6.88(s,1H),6.71(d,J=8.7Hz,2H),5.76(dd,J=10.0,6.4Hz,1H),4. 62–4.52(m,1H),3.74(s,3H),3.21–3.13(m,1H),3.11–3.04(m,1H),2.75–2.65(m, 1H),2.33(s,3H),2.29(s,3H),2.27(s,3H),1.96–1.90(m,1H),1.37–1.27(m,1H). 13 C NMR (101MHz, CDCl3) δ194.7,161.5,156.5,154.4,154.2,144.4,137.8,137.2,136.8,135.2,134.3,133.4 ,130.3,130.0,129.8,129.3,113.3,106.8,55.3,49.3,26.4,20.9,19.9,18.9,18.3.HRMS(ESI)calcd.for C 28 H 30 N3O2 + (M+H) + :440.2333,Found:440.2331.

[0139] Example 12

[0140] A method for preparing ethyl(2E,4E)-1-me-trimethylphenyl-4-(trifluoromethyl)-1,6,7,8-tetrahydroazacyclooctyl-3-carboxylic acid ester, comprising the following steps:

[0141] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 66.4 mg (0.4 mmol, 2.0 equiv) of ethyl 4,4,4-trifluoro-2-butynedioate (2d), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA) and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to give ethyl (2E,4E)-1-trimethyl-4-(trifluoromethyl)-1,6,7,8-tetrahydroazacyclooctyl-3-carboxylic acid ester (3l). The reaction formula is as follows:

[0142]

[0143] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0144] After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3l, which was a white solid with a yield of 78%. 1 H NMR(400MHz, CDCl3)δ7.40(s,1H),6.90(s,2H),6.10(dd,J=10.3,6.3Hz,1H),4.45–4.33(m,1H),4.28–4.15(m,1H),4.14–3.98(m,1H),2 .99–2.85(m,2H),2.59–2.51(m,1H),2.33(s,3H),2.28(s,3H),2.16(s,3H),1.97–1.84(m,1H),1.33–1.27(m,1H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.1,151.1,144.6,137.6,135.6,134.2,132.4(q,J CF =3.9Hz),129.9,129.6,124.1(q,J CF =274.8Hz),91.0,60.1,48.1,25.3,20.9,20.2,18.9,18.1,14.2. 19 F NMR(376MHz,CDCl3)δ-59.6.HRMS(ESI)calcd.forC 20 H 25 F3NO2 + (M+H) + :368.1832,Found:368.1828.

[0145] Example 13

[0146] A method for preparing (2E,4Z)-1-metrimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooctyl-3-carboxaldehyde includes the following steps:

[0147] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 39.0 mg (0.4 mmol, 1.5 equiv) of phenylpropynaldehyde (2e), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA) and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to give (2E,4Z)-1-trimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooctyl-3-carboxaldehyde (3m). The reaction formula is as follows:

[0148]

[0149] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0150] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3m, which was a yellow solid with a yield of 33%. 1 H NMR(400MHz, CDCl3)δ8.85(s,1H),7.42–7.36(m,2H),7.29–7.20(m,2H),7.20–7.14(m,1H),6.88(s,2H),6.88(br,1H),5.71(t,J=8.2Hz,1 H),4.57–4.46(m,1H),2.99–2.78(m,2H),2.53–2.45(m,1H),2.32(s,3H),2.23(s,3H),2.17(s,3H),1.92–1.81(m,1H),1.28–1.18(m,1H). 13 C NMR (101MHz, CDCl3) δ189.9,144.3,142.2,138.0,135.3,134.2,130.0,129.8,128.3,126.8,126.2,49.4,26.1,20.9,18.8,18.1.HRMS(ESI)calcd.for C 23 H 26 NO + (M+H) + :332.2009,Found:332.2007.

[0151] Example 14

[0152] A method for preparing 1-((2E,4Z)-1-metrimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooct-3-yl)ethyl-1-one, comprising the following steps:

[0153] In a nitrogen-filled glove box, 40.7 mg (0.2 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 57.7 mg (0.4 mmol, 2.0 equiv) of 4-phenylbut-3-yn-2-one (2f), 10 mg (0.02 mmol, 10.0 mol%) of catalyst (LA) and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to obtain 1-((2E,4Z)-1-trimethylphenyl-4-phenyl-1,6,7,8-tetrahydroazacyclooct-3-yl)ethyl-1-one (3n). The reaction formula is as follows:

[0154]

[0155] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0156] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3n, which was a white foamy solid with a yield of 62%. 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.54–7.47(m,2H),7.38–7.32(m,2H),7. 29–7.25(m,1H),6.93(s,2H),5.80(dd,J=10.0,6.0Hz,1H),4.58–4.47(m,1 H),3.09–3.00(m,1H),2.96–2.88(m,1H),2.63–2.51(m,1H),2.39(s,3H),2 .30(s,3H),2.22(s,3H),2.00–1.89(m,1H),1.76(s,3H),1.36–1.25(m,1H). 13 C NMR (101MHz, CDCl3) δ198.2,150.6,144.8,144.0,141.4,137.3,135.4,134.2,129.8,129.6,128 .6,127.3,126.8,126.4,108.3,48.7,28.1,26.4,22.2,20.9,18.9,18.2.HRMS(ESI)calcd.forC 24 H 28 NO + (M+H) + :346.2165,Found:346.2164.

[0157] Example 15

[0158] A method for preparing 1-meta-trimethylazinecyclooctane includes the following steps:

[0159] S1, In a nitrogen-filled glove box, 203.3 mg (1 mmol, 1.0 equiv) of 1-trimethylphenylpiperidine (1j), 168 mg (2 mmol, 2.0 equiv) of methyl propynate (2g), 51.2 mg (0.1 mmol, 10.0 mol%) of catalyst (LA), 10.7 mg (0.1 mmol, 10.0 mol%) of 2,6-dimethylpyridine, and 5 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 24 hours to obtain methyl(2E,4Z)-1-trimethylphenyl-1,6,7,8-tetrahydroazacyclooctyl-3-carboxylic acid ester (3o). The reaction formula is as follows:

[0160]

[0161] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0162] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3o, which was a white solid with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.34 (s, 1H), 6.90 (s, 2H), 6.46 (d, J = 10.8Hz, 1H), 5.35–5.2 4(m,1H),3.65(s,3H),2.85–2.45(m,2H),2.33–2.15(m,10H),1.89–1.19(m,3H). 13 CNMR(101MHz, CDCl3)δ170.0,149.8,144.6,137.3,135.3,129.6,127.6,123.1,95.9,51.2,49.2,24.9,20.9,18.6,17.5.HRMS(ESI)calcd.for C 18 H 23 NNaO2 + (M+Na) + :308.1621,Found:308.1623.

[0163] S2, 182.6 mg (0.64 mmol, 1.0 equiv) of the obtained methyl (2E, 4Z)-1-metrimethylphenyl-1,6,7,8-tetrahydroazacyclooctyl-3-carboxylic acid ester (3o) was added to a 25 mL sealed tube, followed by a 3:1 mixture of methanol and water (6 mL: 2 mL), and 153.6 mg (3.84 mmol, 6.0 equiv) of sodium hydroxide. The mixture was heated under reflux at 110 °C for 8 hours. The reaction is shown in the following formula:

[0164]

[0165] After the reaction was complete, the mixture was cooled to room temperature, and 2M hydrochloric acid was carefully added dropwise to adjust the pH of the system to 7. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the corresponding carboxylic acid. No purification was required, and the mixture was directly added to the next step.

[0166] S3, the carboxylic acid obtained in the previous step was directly added to a 20mL hydrogenation vial, along with a 1:1 mixture of dichloromethane and ethanol (4.0mL:4.0mL), and 40mg (10wt%) of palladium on carbon. The vial was then placed in an autoclave, purged with hydrogen three times, and finally purged with hydrogen to adjust the pressure to 2MPa. The reaction was carried out at room temperature for 24 hours. The reaction equation is as follows:

[0167]

[0168] After the reaction was completed, the remaining hydrogen gas was released. The palladium on carbon was removed by diatomaceous earth filtration, the organic phase was dried by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3p, which was a colorless oil with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ6.87(s,2H),3.14–3.07(m,4H),2.32(s,6H),2.27(s,3H),1.88–1.81(m,2H),1.78–1.70(m,4H),1.70–1.61(m,4H). 13 C NMR(101MHz, CDCl3)δ150.4,137.3,134.4,129.8,55.2,29.9,26.9,26.3,20.8,19.6.HRMS(ESI)calcd.for C 16 H 26 N + (M+H) + :232.2060,Found:232.2062.

[0169] Example 16

[0170] A method for preparing 1-meta-trimethylazinecyclodecane includes the following steps:

[0171] S1, In a nitrogen-filled glove box, 92.6 mg (0.4 mmol, 1.0 equiv) of 1-trimethylazinecyclooctane (3p), 67.2 mg (0.8 mmol, 2.0 equiv) of methyl propynate (2g), 20.5 mg (0.04 mmol, 10.0 mol%) of catalyst (LA), 4.3 mg (0.04 mmol, 10.0 mol%) of 2,6-dimethylpyridine, and 2 mL of 1,4-dioxane were added to a 10 mL sealed tube. The mixture was stirred and reacted at 140 °C for 24 hours to obtain methyl(2E,4Z)-1-trimethylphenyl-1,6,7,8,9,10-hexahydroazinecyclodec-3-carboxylic acid ester (3q). The reaction formula is as follows:

[0172]

[0173] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0174] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3q, which was a white solid with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ7.33 (s, 1H), 6.90 (s, 2H), 6.20 (d, J = 10.9Hz, 1H), 5.66– 5.55(m,1H),3.64(s,3H),2.50–2.35(m,3H),2.28(s,9H),1.86–1.27(m,7H). 13 CNMR(101MHz, CDCl3)δ170.7,148.4,142.8,137.0,135.6,133.7,129.9,124.4,95.2,51.2,48.7,28.5,28.3,27.4,27.2,20.8.HRMS(ESI)calcd.for C 20 H 27 NNaO2 + (M+Na) + :336.1934,Found:336.1937.

[0175] S2, 81.5 mg (0.26 mmol, 1.0 equiv) of the obtained methyl (2E, 4Z)-1-mesotrimethylphenyl-1,6,7,8,9,10-hexahydroazacyclodec-3-carboxylic acid ester (3q) was added to an 8 mL reaction flask, along with a 3:1 mixture of methanol and water (3.0 mL: 1.0 mL), and 62.4 mg (1.56 mmol, 6.0 equiv) of sodium hydroxide. The mixture was heated under reflux at 110 °C for 8 hours. The reaction is shown in the following formula:

[0176]

[0177] After the reaction was complete, the mixture was cooled to room temperature, and 2M hydrochloric acid was carefully added dropwise to adjust the pH of the system to 7. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the corresponding carboxylic acid. No purification was required, and the mixture was directly added to the next step.

[0178] S2, the carboxylic acid obtained in the previous step was directly added to a 10mL hydrogenation vial, along with a 1:1 mixture of dichloromethane and ethanol (2mL:2mL), and 18mg (10wt%) of palladium on carbon. The vial was then placed in an autoclave, purged with hydrogen three times, and finally purged with hydrogen to adjust the pressure to 2MPa. The reaction was carried out at room temperature for 24 hours. The reaction equation is as follows:

[0179]

[0180] After the reaction was completed, the remaining hydrogen gas was released. The palladium on carbon was removed by diatomaceous earth filtration, the organic phase was dried by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3r, which was a colorless oil with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ6.86(s,2H),3.17–3.10(m,4H),2.34(s,6H),2.26(s,3H),1.87–1.78(m,4H),1.67–1.60(m,6H),1.56–1.50(m,4H). 13 C NMR(101MHz, CDCl3)δ148.0,137.9,134.6,130.0,53.0,29.0,27.0,26.0,23.8,20.8,19.9.HRMS(ESI)calcd.for C 18 H 30 N + (M+H) + :260.2373,Found:260.2375.

[0181] Example 17

[0182] A method for preparing 1-meta-trimethylazine dodecane includes the following steps:

[0183] S1, in a nitrogen-filled glove box, 51.9 mg (0.2 mmol, 1.0 equiv) of 1-me-trimethylaziridine (3r), 33.6 mg (0.4 mmol, 2.0 equiv) of methyl propynate (2 g), 10.3 mg (0.02 mmol, 10.0 mol%) of catalyst (LA), 2.1 mg (0.02 mmol, 10.0 mol%) of 2,6-dimethylpyridine, and 1 mL of 1,4-dioxane were added to a 10 mL sealed tube. The mixture was stirred and reacted at 140 °C for 24 hours to obtain methyl(2E,4Z)-1-me-trimethylphenylaziridine-dodecane-2,4-diene-3-carboxylic acid ester (3s). The reaction formula is as follows:

[0184]

[0185] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0186] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3s, which was a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ7.14(s,1H),6.90(s,2H),6.39(d,J=15.6Hz,1H),5.78–5.64(m,1H),3.64(s,3H),3.63–3.58(m,2H),2.39–2. 30(m,2H),2.27(s,3H),2.24(s,6H),1.80–1.68(m,2H),1.60–1.52(m,2H),1.43–1.39(m,2H),1.34–1.26(m,2H),1.26–1.20(m,2H). 13 C NMR (101MHz, CDCl3) δ170.2,147.3,144.3,136.9,135.1,133.5,129.6,123.9,9 6.9,51.6,51.1,30.7,24.7,24.5,24.0,20.9,20.9,18.4.HRMS(ESI)calcd.for C 22 H 31 NNaO2 + (M+Na) + :364.2247,Found:364.2245.

[0187] S2, 41.0 mg (0.12 mmol, 1.0 equiv) of the obtained methyl (2E, 4Z)-1-mesotrimethylphenylazacyclododecane-2,4-diene-3-carboxylic acid ester (3s) was added to an 8 mL reaction flask, along with a 3:1 mixture of methanol and water (1.2 mL: 0.4 mL), and 28.8 mg (0.72 mmol, 6.0 equiv) of sodium hydroxide. The mixture was heated under reflux at 110 °C for 8 hours. The reaction is shown in the following formula:

[0188]

[0189] After the reaction was complete, the mixture was cooled to room temperature, and 2M hydrochloric acid was carefully added dropwise to adjust the pH of the system to 7. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the corresponding carboxylic acid. No purification was required, and the mixture was directly added to the next step.

[0190] S2, the carboxylic acid obtained in the previous step was directly added to a 10 mL hydrogenation vial, along with a 1:1 mixture of dichloromethane and ethanol (1 mL:1 mL), and 8 mg (10 wt%) of palladium on carbon. The vial was then placed in an autoclave, purged with hydrogen three times, and finally purged with hydrogen to adjust the pressure to 2 MPa. The reaction was carried out at room temperature for 24 hours. The reaction equation is as follows:

[0191]

[0192] After the reaction was completed, the remaining hydrogen gas was released. The palladium on carbon was removed by diatomaceous earth filtration, the organic phase was dried by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3t, which was a colorless oil with a yield of 87%. 1 H NMR (400MHz, CDCl3) δ6.84(s,1H),6.82(s,1H),3.14–3.09(m,2H),3.05–2.99(m,2H) ,2.33(s,6H),2.24(s,3H),1.84–1.78(m,2H),1.68–1.58(m,6H),1.55–1.37(m,10H). 13 C NMR(101MHz, CDCl3)δ146.8,137.9,134.5,130.0,53.0,50.6,29.0,27.0,26.0,25.2,24.4,23.8,23.0,20.8,20.1,19.9.HRMS(ESI)calcd.for C 20 H 34 N + (M+H) + :288.2686,Found:288.2681.

[0193] Example 18

[0194] A method for preparing (3S,4R)-3-((benzo[d][1,3]dioxol-5-oxy)methyl)-4-(4-fluorophenyl)azacyclooctane, comprising the following steps:

[0195] S1, In a nitrogen-filled glove box, 83.9 mg (0.2 mmol, 1.0 equiv) of N-benzylparoxetine (3u), 33.6 mg (0.4 mmol, 2.0 equiv) of methyl propynate (2g), 20.6 mg (0.04 mmol, 20.0 mol%) of catalyst (LA), 2.1 mg (0.02 mmol, 10.0 mol%) of 2,6-dimethylpyridine, and 1 mL of 1,4-dioxane were added to a 10 mL sealed tube. The mixture was stirred and reacted at 160 °C for 16 hours to obtain (3v). The reaction formula is as follows:

[0196]

[0197] In this example, the catalyst LA is the same as that in Example 7, which is B(C6F5)3;

[0198] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3V, which was a light yellow solid with a yield of 47%. 1 H NMR(400MHz, CDCl3)δ8.02(s,1H),7.60–7.51(m,3H),7.46–7.35(m,4H),7.28–7.19(m,2H),6.88(d,J =8.5Hz,1H),6.64(dd,J=10.7,1.2Hz,1H),6.56(d,J=2.5Hz,1H),6.36(dd,J=8.5,2.5Hz,1H),6.12(q ,J=1.4Hz,2H),5.37(dd,J=10.7,8.5Hz,1H),4.69(d,J=15.3Hz,1H),4.58(dd,J=14.5,2.8Hz,1H),4. 35(d,J=15.3Hz,1H),3.92(s,3H),3.89–3.78(m,3H),3.55(dd,J=14.5,2.8Hz,1H),2.18–2.07(m,1H). 13CNMR(101MHz, CDCl3)δ170.0,163.0,160.5,153.5,151.3,148.5,142.0,138.6,138.6,137.0,129.2,129.1,128.9,128.1,1 28.0,127.5,125.8,115.9,115.7,108.1,105.4,101.3,97.8,95.4,68.3,63.0,51.4,45.6,45.3,33.9.HRMS(ESI)calcd.for C 30 H 28 FNNaO5 + (M+Na) + :524.1844,Found:524.1847.

[0199] S2, 47.1 mg (0.09 mmol, 1.0 equiv) of the obtained methyl (2E, 4Z, 6R, 7S)-7-((benzo[d][1,3]dioxo-5-oxy)methyl)-1-benzyl-6-(4-fluorophenyl)-1,6,7,8-tetrahydroazacyclooctyl-3-carboxylic acid ester (3v) was added to an 8 mL reaction flask, followed by a 3:1 mixture of methanol and water (1.2 mL: 0.4 mL), and 43.2 mg (1.08 mmol, 12.0 equiv) of sodium hydroxide. The mixture was heated under reflux at 110 °C for 8 hours. The reaction is shown in the following formula:

[0200]

[0201] After the reaction was complete, the mixture was cooled to room temperature, and 2M hydrochloric acid was carefully added dropwise to adjust the pH of the system to 7. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the corresponding carboxylic acid. No purification was required, and the mixture was directly added to the next step.

[0202] S2, the carboxylic acid obtained in the previous step was directly added to a 10mL hydrogenation vial, along with 1.5mL of ethanol solvent and 10mg (10wt%) of palladium on carbon. The vial was then placed in an autoclave, purged with hydrogen three times, and finally the pressure was adjusted to 5MPa. The reaction was carried out at room temperature for 24 hours. The reaction equation is as follows:

[0203]

[0204] After the reaction was completed, the remaining hydrogen gas was released. The palladium on carbon was removed by diatomaceous earth filtration, the organic phase was dried by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3w, which was a colorless oil with a yield of 68%. 1H NMR (400MHz, CDCl3) δ7.20–7.11(m,2H),7.00–6.91(m,2H),6.57(d,J=8.4Hz,1H),6.37(d,J=2.5Hz,1H),6.12(dd,J=8.4,2.5Hz,1H),5.8 4(s,2H),3.68–3.48(m,4H),3.34–3.21(m,2H),3.09–3.00(m,1H),2.53–2.47(m,1H),2.15–2.01(m,3H),1.94–1.68(m,3H),1.25(s,1H). 13 C NMR(101MHz,CDCl3)δ161.6(d,J CF =244.8Hz),153.8,148.2,142.0,141.1(d,J CF =3.3Hz), 128.8(d,J CF =7.2Hz), 115.7(d,J CF =21.1Hz),107.9,106.0,101.2,98.4,70.0,46.0,45.7,43.7,41.5,33.3,24.9,23.3. 19 F NMR(376MHz,CDCl3)δ-116.0.HRMS(ESI)calcd.for C 21 H 25 FNO3 + (M+H) + :358.1813,Found:358.1813.

[0205] Example 19

[0206] A method for preparing dimethyl 1-benzyl-6,7-dihydro-1H-azelazone-3,4-dicarboxylate includes the following steps:

[0207] In a nitrogen-filled glove box, 32.5 mg (0.2 mmol, 1.0 equiv) of 1-benzylpyrrolidine (1k), 56.8 mg (0.4 mmol, 2.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst, 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl 1-benzyl-6,7-dihydro-1H-azetop-3,4-dicarboxylic acid (3x). The reaction formula is as follows:

[0208]

[0209] The catalyst used is the same as in Example 1, namely B(2,4,6-F3C6H2)3.

[0210] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3x, which was a light yellow oil with a yield of 71%. 1 H NMR (400MHz, CDCl3) δ7.79 (s, 1H), 7.39–7.30 (m, 3H), 7.24–7.20 (m, 2H), 6.39 (t, J = 7. 3Hz,1H),4.41(s,2H),3.73(s,3H),3.68(s,3H),3.31–3.27(m,2H),2.51–2.44(m,2H). 13 C NMR(101MHz, CDCl3)δ170.0,169.2,148.3,135.8,134.0,133.5,129.0,128.2,127.6,95.1,64.0,52.0,51.9,51.4,29.5.HRMS(ESI)calcd.for C 17 H 19 NNaO4 + (M+Na) + :324.1206,Found:324.1206.

[0211] Example 20

[0212] A method for preparing dimethyl(2E,4E)-1-benzyl-1,6,7,8-tetrahydroazacyclooctyl-3,4-dicarboxylic acid ester includes the following steps:

[0213] In a nitrogen-filled glove box, 35.1 mg (0.2 mmol, 1.0 equiv) of 1-benzylpiperidine (1l), 28.4 mg (0.2 mmol, 1.0 equiv) of dimethyl butynedioate (2a), 8 mg (0.02 mmol, 10.0 mol%) of catalyst, 2.2 mg (0.01 mmol, 5.0 mol%) of trimethylsilyl trifluoromethanesulfonate, and 1 mL of 1,4-dioxane were added to an 8 mL reaction flask. The mixture was stirred and reacted at 140 °C for 12 hours to obtain dimethyl (2E,4E)-1-benzyl-1,6,7,8-tetrahydroazacyclooctyl-3,4-dicarboxylic acid ester (3y). The reaction formula is as follows:

[0214]

[0215] The catalyst used is the same as in Example 1, namely B(2,4,6-F3C6H2)3.

[0216] After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain product 3x, which was a light yellow solid with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ7.71(s,1H),7.35–7.28(m,3H),7.25–7.21(m,2H),6.29(dd,J=10.1,6.9Hz,1H),4.29(d,J=15.0Hz,1H),4.23(d,J=15. 0Hz,1H),3.89–3.82(m,1H),3.71(s,3H),3.61(s,3H),2.73(dd,J=14. 4,4.4Hz,1H),2.43–2.30(m,2H),1.42–1.33(m,1H),1.02–0.94(m,1H). 13 C NMR(101MHz, CDCl3)δ169.8,169.4,150.8,136.1,134.9,133.6,128.9,128.3,128.0,92.6,62.0,52.0,51.3,44.6,25.2,16.9.HRMS(ESI)calcd.for C 18 H 22 NO4 + (M+H) + :316.1543,Found:316.1542.

Claims

1. A method for preparing ring-extended amines or chain-elongated amines from saturated amines, characterized in that, Includes the following steps: In a glove box filled with nitrogen or inert gas, a saturated amine, a first solvent, an alkyne, and a first catalyst are added to the first reaction vessel. The mixture is stirred at 100-160°C to allow for a complete ring-expansion reaction, yielding a ring-expanded amine or a chain-extended amine, wherein: The saturated amine has the following structure: The structural formula of the alkyne is: The first catalyst is triarylborane, and its molar ratio with the saturated amine is (10-20):

100.

2. The method according to claim 1, characterized in that: In the structural formula, n is 0 to 10; X is 0 or S; The structural formula of the triarylborane is B(R) 11 )3, where R 11 It is a phenyl, pentafluorophenyl, 3,5-di(trifluoromethyl)-substituted phenyl or 2,4,6-trifluoro-substituted phenyl.

3. The method according to claim 2, characterized in that, The reaction formula for the ring expansion reaction is as follows: in: R 1 It is alkyl, aryl, or substituted aryl; R 2 and R 3 Each group is independently selected from hydrogen, alkyl, amino, ether, ester, aryl, substituted aryl, and heteroaryl groups; R 4 It can be hydrogen, alkyl, amino, ester, aryl, substituted aryl, or heteroaryl; R 5 R 6 R 7 Each is independently selected from alkyl, aryl, and substituted aryl groups; R 8 It can be alkyl, aryl, substituted aryl, or heteroaryl; R 9 and R 10 Each group is independently selected from hydrogen, alkyl, ester, cyano, carbonyl, aldehyde, trifluoromethyl, sulfonyl, aryl, substituted aryl, and heteroaryl groups; The first solvent is tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, or an aromatic solvent, and the amount of the first solvent is sufficient to dissolve all the raw materials; When with R 1 R 5 R 6 Or R 7 When the amine is alkyl, trimethyl trifluoromethanesulfonate is added as an additive, and the molar ratio of trimethyl trifluoromethanesulfonate to the saturated amine is 5:

100. When R 9 For CO2Me, R 10 When hydrogen is used, 2,6-dimethylpyridine is added as an additive, and the molar ratio of 2,6-dimethylpyridine to the saturated amine is 10:

100.

4. The method according to claim 1, characterized in that: The equivalence ratio of the alkyne to the saturated amine is (1-2):1; the ring expansion reaction takes 12-24 hours.

5. The method according to any one of claims 2 to 4, characterized in that, When R 9 For CO2Me, R 10 When the hydrogen is used, the method further includes the following steps: Hydrolysis reaction: The obtained ring-expanding amine or chain-extending amine, along with a second solvent and a base, are added to the second reaction vessel. The mixture is stirred at 100–110 °C to allow for complete hydrolysis, yielding the corresponding carboxylic acid. The reaction formula is as follows: Reduction reaction: At room temperature, the carboxylic acid obtained from the hydrolysis reaction, the third solvent, and the second catalyst are added to the third reaction vessel. Then, the third reaction vessel is placed in an autoclave, hydrogen gas is introduced, and the mixture is stirred to allow the reaction to proceed fully, yielding a completely reduced amine. The reaction equation is as follows: In the above hydrolysis reaction: The base is NaOH, LiOH or KOH, and the equivalent ratio of base to substrate is (6-12):1; The second solvent is a mixture of water and methanol, with a volume ratio of 1:

3. Hydrolysis time is 2–12 hours; In the reduction reaction described above: The second catalyst is palladium on carbon, with an equivalence ratio of palladium on carbon to substrate of (10–30):

100. The third solvent is a mixture of dichloromethane and ethanol, with a volume ratio of 1:1; the hydrogen gas pressure is 20-50 MPa. The reduction reaction time is 24 to 48 hours.

6. The method according to claim 5, characterized in that: When R 1 When the aryl group is substituted, the substituted aryl group is 2,4,6-trimethylphenyl or 2,6-dimethyl-4-methoxyphenyl; When R 5 R 6 Or R 7 When the aryl group is substituted, the substituted aryl group is 2,4,6-trimethylphenyl or 2,6-dimethyl-4-methoxyphenyl.

7. The method according to claim 5, characterized in that: The R 2 When the R is a heteroaryl group, the heteroaryl group is furanyl or thiophene; 3 When the aryl group is a heteroaryl group, the heteroaryl group is furanyl, thiophenyl, or pyridyl; the R 4 When the heteroaryl group is a furanyl, thiophene, or pyridyl group, the heteroaryl group is a furanyl, thiophene, or pyridyl group.

8. The method according to claim 5, characterized in that: The R 8 When the heteroaryl group is a furanyl, thiophene, or pyridyl group, the heteroaryl group is a furanyl, thiophene, or pyridyl group.

9. The method according to claim 5, characterized in that: The R 9 When the heteroaryl group is a furanyl, thiophene, pyridinyl, or pyrimidinyl group, the heteroaryl group is used.

10. The method according to claim 5, characterized in that: The R 10 When the heteroaryl group is a furanyl, thiophene, pyridinyl, or pyrimidinyl group, the heteroaryl group is used.

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