Chiral silatetrahydro-1-naphthylamine compound and synthesis method thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral silatetrahydro-1-naphthylamine compound and a synthesis method thereof. The synthesis method of the chiral silatetrahydro-1-naphthylamine compound comprises the following steps: in an inert atmosphere, mixing a palladium catalyst, a chiral phosphine ligand and an organic solvent, pre-stirring, then adding N-allenamine, cooling to a reaction temperature, adding benzosilacyclobutane, carrying out a reaction, and after the reaction is finished, carrying out separation and purification to obtain the chiral silatetrahydro-1-naphthylamine compound. The chiral silicon hybrid tetrahydro-1-naphthylamine compound is obtained. The raw materials benzo-silazane and N-allenamine can be prepared by a simple method, and the method has the advantages of high selectivity, high yield, mild conditions, wide substrate range, simplicity and convenience in operation and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a chiral silanetetrahydro-1-naphthylamine compound and its synthesis method. Background Technology

[0002] The chiral tetrahydronaphthylamine skeleton is widely considered a "preferred structure" in medicinal chemistry due to its flexible yet rigid ring system and functionalizable sites (such as amino and aromatic groups). This skeleton not only mimics the core of many bioactive natural products but also exhibits excellent binding potential in drug design due to its unique conformation and spatial orientation. Specifically, its derivatives have been shown to be potent inhibitors of serotonin reuptake, such as P2X3 and P2X. 2 / 3 Receptor blockers and β3-adrenergic receptor antagonists constitute the core of lead compounds and clinical drug candidates with significant antidepressant and anti-inflammatory activities (see below). However, their biological activity is highly dependent on the absolute configuration of the amino group. Therefore, developing efficient and highly selective methods for the stereospecific synthesis of chiral tetrahydronaphthylamines (especially controlling the chiral amino group) is not only a challenge in synthetic chemistry but also a key strategy for improving the druggability parameters of such molecules (such as target selectivity, metabolic stability, and reducing off-target toxicity). Precise control of chirality can greatly optimize drug-target interactions, thereby significantly expanding the depth and breadth of its application in modern drug discovery.

[0003]

[0004] Silicon heterocycles are one of the most important core frameworks in silicon-containing functional molecules, and due to their unique physicochemical properties, silicon heterocyclic skeletons have wide applications in organic synthesis, materials science, and biomedicine. In medicinal chemistry, the introduction of silicon atoms into bioactive molecules has attracted widespread attention because silicon-based bioisosteres typically exhibit higher metabolic stability, better lipophilicity, and unique three-dimensional structures compared to their carbon analogs. Silyl heterocyclic butanes are among the most important silicon-based synthons, and their high ring strain (150 kJ / mol) and unique Lewis acidity make them suitable for the synthesis of specific silicon-containing compounds. Organic nitrogen-containing compounds are also a very important class of compounds, with applications in pesticides, pharmaceuticals, aerospace, and many other fields. Therefore, the green and efficient construction of silicon heterocyclic compounds while introducing nitrogen atoms is of great significance for the synthesis of compounds with diverse functions.

[0005]

[0006] Despite their demonstrated potential, the physicochemical properties of chiral silyro-tetrahydro-1-naphthylamine analogs remain largely unknown. This significant knowledge gap stems primarily from the persistent limitations of efficient and precise synthetic methods. Therefore, developing a simple, effective, and efficient synthetic method for constructing compounds with excellent stereoselectivity is crucial to unlocking their untapped pharmacological potential. The ring-expansion reaction of benzo[a]silane compounds offers a unique strategy for the synthesis of silane heterocyclic compounds. Currently, this strategy has been successfully applied to the cycloaddition reactions of benzo[a]silane butane with alkenes, alkynes, small rings, and carbonyl compounds, constructing structurally diverse 5-7 membered silane heterocyclic compounds. Although many challenges in the ring-expansion reactions of benzo[a]silane butane have been overcome, its cycloaddition reaction with allenes remains highly challenging due to the difficulty in controlling the regio, chemo, and configurational selectivity of such reactions. N-Allenes, however, exhibit unique reactivity and selectivity compared to common allenes. Therefore, we hypothesize the possibility of generating chiral silyro-tetrahydro-1-naphthylamine compounds through the selective asymmetric cycloaddition reaction of benzo[a]silane butane with N-allenes. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing chiral silane tetrahydro-1-naphthylamine compounds, which has the advantages of high selectivity, high yield, mild conditions, wide substrate range and simple operation.

[0008] A first aspect of the present invention provides a method for synthesizing a chiral silylated tetrahydro-1-naphthylamine compound, comprising: Under an inert atmosphere, palladium catalyst, chiral phosphine ligand and organic solvent were mixed and pre-stirred, then compound 2 as shown in Formula 2 was added, and after cooling to the reaction temperature, compound 1 as shown in Formula 1 was added to react. After the reaction was completed, the chiral silytetrahydro-1-naphthylamine compound as shown in Formula 3 was obtained by separation and purification. The synthetic route is as follows: ; R is selected from Me, Et, n -hex, n -Bu, Ph, F, Cl, Br, I, One of them; R1 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R2 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R3 is selected from Me, CH3(CH2) nCH2, Ph, Bn, Boc, , , , , , , , , , , , , , , , , , , , , , , One of them; PG is selected from , , , , , , , , , One of them.

[0009] Further, the molar ratio of compound 1, compound 2, palladium catalyst, and chiral phosphine ligand is (1.1~3):1:(0.025~0.1):(0.025~0.1).

[0010] Furthermore, the molar concentration of compound 2 in the reaction system composed of compound 1, compound 2, palladium catalyst, chiral phosphine ligand and organic solvent is 0.1 mol / L to 0.2 mol / L.

[0011] Furthermore, the palladium catalyst is selected from one or more of bis(dibenzylacetone)palladium, tri(dibenzylacetone)dipalladium, palladium acetate, di-tert-butylpalladium, allyl palladium chloride dimer, palladium trifluoroacetate, di-M-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium, and cyclopentadienylallylpalladium.

[0012] Furthermore, the chiral phosphine ligand is selected from one of formulas L1 to L12; wherein, formulas L1 to L12 are:

[0013] .

[0014] Furthermore, the organic solvent is selected from one or more of toluene, trifluorotoluene, o-difluorobenzene, hexafluorobenzene, acetone, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, carbon tetrachloride, dichloromethane, chloroform, and dichloroethane.

[0015] Furthermore, the organic solvent is a drying solvent.

[0016] Furthermore, the reaction temperature is from -20 ℃ to 80 ℃, and the reaction time is from 12 h to 48 h.

[0017] Furthermore, the reaction is carried out in the following order: first, the palladium catalyst and the chiral phosphine ligand are dissolved in the organic solvent, then compound 2 is added, the temperature is adjusted to the reaction temperature, and finally compound 1 is added. Alternatively, the palladium catalyst and the chiral phosphine ligand are first dissolved in the organic solvent, then compound 2 and the organic solvent are added, the temperature is adjusted to the reaction temperature, and finally compound 1 is added.

[0018] In a second aspect, the present invention provides a chiral silanetetrahydro-1-naphthylamine compound synthesized according to the above method.

[0019] Compared with the prior art, the present invention has at least the following beneficial effects: The method for synthesizing chiral silylatetetrahydro-1-naphthylamine provided by this invention uses readily available benzosilylate (compound 1) and N-allenamine (compound 2) as starting materials, and selectively adds them in a palladium catalyst and chiral phosphine ligand catalytic system to generate chiral silylatetetrahydro-1-naphthylamine compounds. It has the advantages of high selectivity, high yield, mild conditions, broad substrate range and simple operation. Detailed Implementation

[0020] To fully understand the purpose, features, and effects of this invention, the following detailed embodiments are provided. Except as described below, the process methods of this invention employ conventional methods or apparatus in the art. Unless otherwise specified, the terms and expressions used below have the meanings commonly understood by those skilled in the art.

[0021] When a range of values ​​is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0022] A first aspect of this invention provides a method for synthesizing a chiral silylated tetrahydro-1-naphthylamine compound, comprising: Under an inert atmosphere, palladium catalyst, chiral phosphine ligand and organic solvent were mixed and pre-stirred, and then N-alleneamine (compound 2) as shown in Formula 2 was added. After cooling to the reaction temperature, benzo[1]silane (compound 1) as shown in Formula 1 was added to carry out the reaction. After the reaction was completed, the chiral silane tetrahydro-1-naphthylamine compound as shown in Formula 3 was obtained by separation and purification. The synthetic route is as follows: ; R is selected from Me, Et, n -hex, n -Bu, Ph, F, Cl, Br, I, One of them; R1 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R2 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R3 is selected from Me, CH3(CH2) n CH2, Ph, Bn, Boc, , , , , , , , , , , , , , , , , , , , , , , One of them; PG is selected from , , , , , , , , , One of them.

[0023] The method for synthesizing chiral silylatetetrahydro-1-naphthylamine provided in this invention involves the selective addition of benzo[a]silazanecyclobutane (compound 1) and N-allenamine (compound 2) in a palladium catalyst and chiral phosphine ligand catalytic system to prepare the chiral silylatetetrahydro-1-naphthylamine compound in one step. Both starting materials, compound 1 and compound 2, can be prepared using simple methods, and the method offers advantages such as high selectivity, high yield, mild conditions, broad substrate range, and ease of operation.

[0024] In some embodiments, the molar ratio of compound 1, compound 2, palladium catalyst, and chiral phosphine ligand is (1.1~3):1:(0.025~0.1):(0.025~0.1). Preferably, the molar ratio of compound 1, compound 2, palladium catalyst, and chiral phosphine ligand is 2:1:0.05:0.05.

[0025] In some embodiments, the molar concentration of compound 2 in the reaction system consisting of compound 1, compound 2, palladium catalyst, chiral phosphine ligand, and organic solvent is 0.1 mol / L to 0.2 mol / L. Preferably, the molar concentration of compound 2 in the reaction system consisting of compound 1, compound 2, palladium catalyst, chiral phosphine ligand, and organic solvent is 0.1 mol / L.

[0026] In some embodiments, the palladium catalyst is selected from one or more of bis(dibenzylacetone)palladium, tris(dibenzylacetone)dipalladium, palladium acetate, di-tert-butylpalladium, allyl palladium chloride dimer, palladium trifluoroacetate, di-M-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium, and cyclopentadienylallylpalladium. Preferably, the palladium catalyst is bis(dibenzylacetone)palladium.

[0027] In some embodiments, the chiral phosphine ligand is selected from one of formulas L1 to L12; preferably, the chiral phosphine ligand is L11. Wherein, formulas L1 to L12 are:

[0028] .

[0029] In some embodiments, the organic solvent is a drying solvent. The organic solvent is selected from one or more of toluene, trifluorotoluene, o-difluorobenzene, hexafluorobenzene, acetone, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, carbon tetrachloride, dichloromethane, chloroform, and dichloroethane. Preferably, the organic solvent is dichloroethane.

[0030] In some embodiments, the reaction temperature is from -20°C to 80°C, and the reaction time is from 12 h to 48 h. Preferably, the reaction temperature is from -20°C to 40°C, and the reaction time is from 36 h to 48 h. More preferably, the reaction temperature is from -20°C, and the reaction time is 48 h.

[0031] In some embodiments, the reaction feed order is as follows: first, palladium catalyst and chiral phosphine ligand are added, then an organic solvent is added for pre-stirring, then compound 2 is added, and finally compound 1 is added.

[0032] A second aspect of the present invention provides a chiral silanetetrahydro-1-naphthylamine compound synthesized according to the above method, the structural formula of which is shown in Formula 3: .

[0033] In this embodiment of the invention, except for compounds 1 and 2 which require synthesis, all other raw materials are commercially available. Specifically, bis(dibenzylacetone)palladium was purchased from Adamas Chemical Company, tris[3,5-bis(trifluoromethyl)phenyl]phosphine was purchased from Leyan Chemical Company, and toluene was purchased from Sinopharm Chemical Reagent Co., Ltd. The sealing tube used is a high-pressure resistant glass reaction tube with a 19 / 22 internal ground joint and a 2 mm glass joint door, preferably a sealing tube that has undergone deoxidation and dehydration treatment.

[0034] Compound 1 was obtained from the literature Wang, XC.; Li, B.; Ju, CW.; Zhao, DB. Nat Commun. 2022 , 13 , 3392. Prepared by the method described above.

[0035] Compound 2 was derived from the literature Suárez-Pantiga, S.; Hernández-Díaz, C.; Rubio, E.; González, JM. Angew. Chem. Int. Ed. 2012, 51 , 11552. Prepared by the method described above.

[0036] Reaction Condition Screening Examples The following describes the screening of addition reaction conditions for the one-step preparation of chiral silanetetrahydro-1-naphthylamine compounds by selective addition of benzo[a]silane-1-cyclobutane (compound 1) and N-allenamine (compound 2) in a palladium catalyst and chiral phosphine ligand catalytic system.

[0037] Example 1: Screening of chiral phosphine ligands Compound 1, dimethylbenzosilane, and compound 2, N-allenamine, were used. PG was selected as (p-toluenesulfonyl, Ts), R as (benzyl, Bn), bis(benzylacetone)palladium was used as the catalyst, toluene was used as the solvent, and the temperature was 40 °C. Chiral phosphine ligands were screened, and the optimal experimental conditions were finally determined to be the L11 chiral phosphine ligand. The reaction formula and experimental results are as follows:

[0038] Reaction conditions: 1a (2.0 equivalents), 2a (0.05 mmol), Pd(dba)2 (2.5 mol%), ligand (6 mol%), toluene solvent (0.1 M), reaction at 40 °C. The total NMR yield of (3a + 4a) and the 3a / 4a ratio were determined by ¹H NMR with pyrazine as an internal standard. The enantiomeric excess of 3a was determined by chiral high-performance liquid chromatography. NR = no reaction.

[0039] It can be seen that the chiral phosphorus ligand L11 showed a significant advantage for the two isomers 3a and 4a, achieving a yield of 90% and an ee value of 60%. In particular, for the reaction with L3 as the ligand, the ratio of 3a: 4a = 1: 2.8 could be increased to >20: 1 after changing to L11, resulting in a significant improvement in selectivity.

[0040] Example 2 Screening of conditions for the addition reaction of alleneamine with silane Based on the optimal experimental conditions in Example 1, this invention compared different palladium catalysts and finally selected the optimal experimental conditions for entry 1. The reaction formula and experimental results are as follows:

[0041]

[0042] It can be seen that using bis(dibenzylacetone)palladium can achieve both good yield and ee value.

[0043] Example 3: Further optimization of reaction conditions Since the yield and ee value in Example 2 were still unsatisfactory, this invention further investigated the effects of solvent, reaction temperature, and reaction time on the reaction. Specific reaction results are shown below: Based on the optimal conditions in Example 2, the reaction conditions were further optimized, and solvent types, reaction temperatures, and reaction times were screened, ultimately resulting in the optimal experimental conditions, entry18.

[0044]

[0045]

[0046] It can be seen that, using bis(dibenzylacetone)palladium as a catalyst, L11 as a ligand, and dichloroethane as a solvent, the reaction was carried out at -20°C for 48 h, achieving a yield of 98% and an ee value of 92%. Furthermore, this yield and ee value maintained good stability in multiple repeated experiments.

[0047] Based on the above-mentioned optimization experiments, the inventors selected the optimal conditions to study the universality of the present invention, as detailed below.

[0048] Example 4 Prepare the compound as shown in the following formula: .

[0049] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 59.9 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 86.0 mg of a colorless gel, with a yield of 96% and an ee value of 92%.

[0050] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.54 – 7.41 (m, 2H), 7.24 – 6.92 (m,10H), 6.81 – 6.66 (m, 1H), 5.72 (dq, J = 3.4, 1.6 Hz, 1H), 5.50 – 5.40 (m,1H), 5.34 (d, J = 3.6 Hz, 1H), 4.66 (dd, J = 16.2, 3.6 Hz, 1H), 4.17 (dd, J =16.1, 3.7 Hz, 1H), 2.39 (d, J = 3.6 Hz, 3H), 1.87 (dd, J = 14.8, 3.5 Hz, 1H), 1.68 (dd, J= 14.9, 3.7 Hz, 1H), 0.30 – 0.13 (m, 3H), -0.17 (d, J = 4.0 Hz, 3H).

[0051] 13 C NMR (100 MHz, Chloroform- d ) δ 147.3, 142.7, 139.0, 137.9, 137.3,136.0, 131.3, 130.9, 129.3, 129.1, 128.2, 128.1, 127.8, 127.4, 126.8, 125.2, 69.4, 51.3, 21.5, 20.7, -2.4, -2.6.

[0052] HRMS(ESI) calcd for C 26 H 30 NO2SSi [M+H] + : 448.1761, found: 448.1761.

[0053] [α]20 D= -18.7 (c = 0.4, CHCl3).

[0054] HPLC conditions: Chiralcel IA column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 9.07 min, t R (minor) = 13.13 min.

[0055] Example 5 Prepare the compound as shown in the following formula: .

[0056] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 63.1 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 77.3 mg of a colorless gel, with a yield of 83% and an ee value of 94%.

[0057] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.57 (d, J = 8.2 Hz, 2H), 7.35 – 7.27(m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.11 – 6.96 (m, 3H), 6.89 – 6.74 (m, 2H), 6.43 – 6.31 (m, 1H), 6.30 – 6.23 (m, 1H), 6.17 (t, J = 2.2 Hz, 1H), 6.02 (s,1H), 5.76 – 5.67 (m, 1H), 3.50 (s, 3H), 2.39 (s, 3H), 1.48 (d, J = 15.0 Hz, 1H), 0.85 (d, J = 15.0 Hz, 1H), 0.09 (s, 3H), -0.23 (s, 3H).

[0058] 13 C NMR(100 MHz, CDCl3) δ 159.3, 148.7, 143.1, 139.5, 138.3, 137.7,136.5, 131.7, 131.5, 131.2, 129.2, 128.8, 128.4, 128.1, 125.7, 125.1, 118.0,115.0, 69.0, 55.2, 21.6, 19.6, -1.9, -2.1. HRMS(ESI) calcd for C 26H 30 NO3SSi [M+H] + : 464.1710, found: 464.1709.

[0059] [α]20 D= -35.3 (c = 0.4, CHCl3).

[0060] HPLC conditions: Chiralcel IC column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 21.54 min, t R (minor) = 25.77 min.

[0061] Example 6 Prepare the compound as shown in the following formula: .

[0062] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 76.9 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silanecyclobutane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 97.2 mg of a colorless gel, with a yield of 97% and an ee value of 90%.

[0063] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d δ 7.98 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.34 – 7.23 (m, 2H), 7.22 – 7.02 (m, 6H), 6.94(d, J = 7.3 Hz, 1H), 6.84 (d, J= 2.3 Hz, 1H), 5.89 (d, J = 1.8 Hz, 1H), 5.60 –5.45 (m, 2H), 3.51 (ddd, J = 14.7, 12.0, 5.0 Hz, 1H), 3.33 (ddd, J = 14.7,11.9, 5.1 Hz, 1H), 2.96 (dtd, J = 36.2, 13.1, 5.0 Hz, 2H), 2.39 (s, 3H), 2.18(d, J = 14.7 Hz, 1H), 1.91 (d, J = 14.7 Hz, 1H), 0.21 (s, 3H), -0.04 (s, 3H)。

[0064] 13 C NMR(100 MHz, CDCl3) δ 147.9, 142.7, 138.5, 138.1, 136.5, 136.1,131.1, 130.8, 129.2, 128.2, 128.0, 127.3, 127.2, 125.5, 121.9, 121.8, 119.2,119.0, 113.3, 111.0, 68.8, 48.9, 26.0, 21.5, 21.2, -2.4, -2.8。

[0065] HRMS(ESI) calcd for C 29 H 33 N2O2SSi [M+H] + : 501.2027, found: 501.2025。

[0066] [α]20 D= -14.9 (c = 0.4, CHCl3)。

[0067] HPLC conditions: Chiralcel IA column, n -hexane / i -PrOH = 75:25, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 6.67 min, t R (minor) =12.02 min。

[0068] Example 7 Prepare the compound as shown in the following formula: .

[0069] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 72.5 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silanecyclobutane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 94.6 mg of a colorless gel, with a yield of 98% and an ee value of 94%.

[0070] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.10 – 7.96 (m, 2H), 7.55 – 7.38 (m,2H), 7.28 – 7.11 (m, 6H), 7.12 – 7.02 (m, 2H), 6.73 – 6.59 (m, 1H), 5.62 (t, J = 1.4 Hz, 1H), 5.49 – 5.39 (m, 2H), 4.82 (d, J = 16.1 Hz, 1H), 4.32 (d, J =16.1 Hz, 1H), 1.82 (d, J = 14.6 Hz, 1H), 1.72 (d, J = 14.7 Hz, 1H), 0.28 (s, 3H), -0.19 (s, 3H).

[0071] 13 C NMR(100 MHz, CDCl3) δ 149.1, 146.8, 145.8, 138.8, 136.7, 135.4,131.7, 130.9, 130.7, 128.8, 128.2, 128.0, 127.9, 127.2, 125.5, 123.3, 69.7,51.8, 20.8, -2.4, -2.6.

[0072] HRMS(ESI) calcd for C 25 H 27 N₂O₄SSi [M+H] + : 479.1455, found: 479.1449.

[0073] [α]20 D= -19.2 (c = 0.4, CHCl3).

[0074] HPLC conditions: Chiralcel ODH column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 12.76 min, t R (minor) = 14.74 min.

[0075] Example 8 Prepare the compound as shown in the following formula: .

[0076] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were first added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 72.9 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silanecyclobutane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 96.7 mg of colorless gel, with a yield of 94% and an ee value of 93%.

[0077] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.42 (dd, J = 8.6, 3.2 Hz, 2H), 7.97(dd, J= 7.4, 1.3 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.39 – 7.32 (m, 1H), 7.33 –7.26 (m, 1H), 7.22 – 7.12 (m, 2H), 7.11 – 7.01 (m, 4H), 6.92 – 6.76 (m, 2H),6.75 – 6.63 (m, 1H), 6.31 – 6.19 (m, 1H), 6.10 (s, 1H), 5.74 – 5.60 (m, 1H),2.87 (s, 6H), 1.31 (d, J = 15.0 Hz, 1H), 0.67 (d, J = 14.9 Hz, 1H), 0.03 (s,3H), -0.28 (s, 3H)。

[0078] 13 C NMR(100 MHz, CDCl3) δ 151.4, 147.9, 139.4, 137.5, 135.9, 135.1,132.7, 132.6, 131.9, 131.2, 131.0, 130.1, 130.0, 129.5, 128.35, 128.34,128.30, 127.5, 125.4, 123.0, 120.3, 114.9, 69.0, 45.4, 19.2, -1.9, -2.2。

[0079] HRMS(ESI) calcd for C 30 H 33 N2O2SSi [M+H] + : 513.2027, found: 513.2026。

[0080] [α]20 D= -45.5 (c = 0.4, CHCl3)。

[0081] HPLC conditions: Chiralcel ODH column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 6.08 min, t R (minor) = 5.32min。

[0082] Example 9 Prepare the compound as shown in the following formula: .

[0083] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were first added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 62.7 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 85.5 mg of colorless gel, with a yield of 93% and an ee value of 93%.

[0084] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.50 (dd, J = 7.2, 1.8 Hz, 1H), 7.21 –7.10 (m, 3H), 7.05 (t, J = 7.6 Hz, 2H), 6.91 – 6.78 (m, 3H), 6.74 (s, 2H), 6.51 (t, J = 1.4 Hz, 1H), 6.28 (s, 1H), 5.86 (dd, J = 2.2, 1.1 Hz, 1H), 2.45(s, 6H), 2.18 (s, 3H), 1.36 (d, J = 6.8 Hz, 1H), 0.48 (d, J = 15.2 Hz, 1H), 0.06 (s, 3H), -0.24 (s, 3H).

[0085] 13C NMR(100 MHz, CDCl3) δ 148.1, 142.3, 140.4, 139.4, 137.1, 136.3,133.4, 133.0, 132.9, 132.3, 131.5, 131.3, 128.4, 128.3, 128.3, 125.6, 67.2, 23.0, 20.8, 19.1, -1.6, -2.2.

[0086] HRMS(ESI) calcd for C 27 H 31 NNaO2SSi [M+Na] + : 484.1737, found: 484.1736.

[0087] [α]20 D= -34.0 (c = 0.4, CHCl3).

[0088] HPLC conditions: Chiralcel IA column, n -hexane / i -PrOH = 95:05, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 7.08 min, t R (minor) = 6.56min.

[0089] Example 10 Prepare the compound as shown in the following formula: .

[0090] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were first added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 44.7 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 72.5 mg of a colorless gel, with a yield of 98% and an ee value of 92%.

[0091] The product structure characterization data are as follows: 1H NMR (400 MHz, Chloroform- d ) δ 7.80 – 7.63 (m, 2H), 7.28 (d, J = 8.0Hz, 2H), 7.17 – 6.98 (m, 3H), 6.93 (d, J = 7.7 Hz, 1H), 5.68 (t, J = 2.0 Hz,1H), 5.61 – 5.46 (m, 2H), 2.64 (s, 3H), 2.43 (s, 3H), 2.21 (d, J = 14.6 Hz, 1H), 2.02 (d, J = 14.6 Hz, 1H), 0.14 (s, 3H), 0.03 (s, 3H).

[0092] 13 C NMR(100 MHz, CDCl3) δ 146.9, 143.1, 137.9, 136.4, 130.9, 129.4,127.7, 127.55, 127.50, 126.4, 125.4, 67.3, 32.2, 21.5, 21.3, -2.6, -2.7.

[0093] HRMS(ESI) calcd for C 20 H 25 NNaO2SSi [M+Na] + : 394.1267, found: 394.1267.

[0094] [α]20 D= -52.4 (c = 0.4, CHCl3).

[0095] HPLC conditions: Chiralcel IA column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 6.11 min, t R (minor) = 6.57min.

[0096] Example 11 Prepare the compound as shown in the following formula: .

[0097] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 57.1 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 84.5 mg of a colorless gel, with a yield of 97% and an ee value of 87%.

[0098] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.58 – 7.50 (m, 2H), 7.36 – 7.27 (m,1H), 7.27 – 7.16 (m, 3H), 7.16 – 7.04 (m, 4H), 6.86 – 6.77 (m, 1H), 6.75 –6.66 (m, 2H), 6.29 (t, J = 1.6 Hz, 1H), 6.02 (s, 1H), 5.72 (dd, J = 2.1, 1.2Hz, 1H), 2.39 (s, 3H), 1.47 (d, J = 15.0 Hz, 1H), 0.83 (d, J = 14.9 Hz, 1H), 0.09 (s, 3H), -0.23 (s, 3H).

[0099] 13 C NMR(100 MHz, CDCl3) δ 148.7, 142.9, 139.2, 137.5, 137.3, 136.4,132.8, 131.6, 131.4, 131.1, 129.1, 128.32, 128.30, 128.2, 127.9, 125.6, 68.9,21.5, 19.4, -2.1, -2.2.

[0100] HRMS(ESI) calcd for C 25 H27 NNaO2SSi [M+Na] + : 456.1424, found: 456.1423.

[0101] [α]20 D= -45.0 (c = 0.4, CHCl3).

[0102] HPLC conditions: Chiralcel IC column, n -hexane / i -PrOH = 80:20, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 12.18 min, t R (minor) = 14.73 min.

[0103] Example 12 Prepare the compound as shown in the following formula: .

[0104] The preparation method is as follows: Under an inert atmosphere in a glove box, bis(dibenzylacetone)palladium (5 mmol%, 5.7 mg), ligand L11 (5 mmol%, 10.1 mg), and dichloroethane (1 mL) were first added to a 10 mL sealed tube and stirred for 10 min. Then, N-allenamine (0.2 mmol, 58.3 mg) and dichloroethane (1 mL) were added. After cooling to -20 °C, benzo[a]silane-butane (0.4 mmol, 59.3 mg) was slowly added dropwise along the wall. Finally, after reacting at -20 °C for 48 hours, the product was purified by column chromatography to obtain 87.7 mg of a colorless gel, with a yield of 99% and an ee value of 90%.

[0105] The product structure characterization data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.60 – 7.47 (m, 1H), 7.33 – 7.25 (m,1H), 7.18 – 7.11 (m, 3H), 7.11 – 6.95 (m, 6H), 6.82 (d, J = 7.3 Hz, 1H), 5.89– 5.73 (m, 1H), 5.49 (d, J= 1.9 Hz, 1H), 5.37 (s, 1H), 4.60 (d, J = 16.1 Hz,1H), 4.13 (d, J = 16.8 Hz, 1H), 1.92 (d, J = 14.9 Hz, 1H), 1.73 (d, J = 14.9 Hz,1H), 0.20 (s, 3H), -0.15 (s, 3H)。

[0106] 13 C NMR(100 MHz, CDCl3) δ 147.6, 141.2, 139.3, 137.0, 136.0, 132.4,131.5, 131.25, 131.23, 129.4, 128.5, 128.3, 128.0, 127.07, 127.05, 125.5,70.1, 51.4, 20.8, -2.3, -2.5。

[0107] HRMS(ESI) calcd for C 23 H 25 NNaO2S2Si [M+Na] + : 462.0988, found: 462.0987。

[0108] [α]20 D= -13.4 (c = 0.4, CHCl3)。

[0109] HPLC conditions: Chiralcel IA column, n -hexane / i -PrOH = 90:10, flowrate = 1.0 mL / min, wavelength = 225 nm, t R (major) = 6.66 min, t R (minor) = 8.50min。

[0110] It will be readily understood by those skilled in the art that the above-described advantageous methods can be freely combined and superimposed without conflict. The above are merely preferred embodiments of this application and are not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application. The above are merely preferred embodiments of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of this application, and these improvements and modifications should also be considered within the protection scope of this application.

Claims

1. A method for synthesizing a chiral silylatetetrahydro-1-naphthylamine compound, characterized in that, include: Under an inert atmosphere, palladium catalyst, chiral phosphine ligand and organic solvent were mixed and pre-stirred, then compound 2 as shown in Formula 2 was added, and after cooling to the reaction temperature, compound 1 as shown in Formula 1 was added to react. After the reaction was completed, the chiral silytetrahydro-1-naphthylamine compound as shown in Formula 3 was obtained by separation and purification. The synthetic route is as follows: ； R is selected from Me, Et, n -hex, n -Bu, Ph, F, Cl, Br, I, One of them; R1 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R2 is selected from Me, Et, n -hex, n -Bu, Ph, One of them; R3 is selected from Me, CH3(CH2) n CH2, Ph, Bn, Boc, , , , , , , , , , , , , , , , , , , , , , , One of them; PG is selected from , , , , , , , , , One of them.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 1, compound 2, palladium catalyst, and chiral phosphine ligand is (1.1~3):1:(0.025~0.1):(0.025~0.1).

3. The synthesis method according to claim 1, characterized in that, The molar concentration of compound 2 in the reaction system consisting of compound 1, compound 2, palladium catalyst, chiral phosphine ligand, and organic solvent is 0.1 mol / L to 0.2 mol / L.

4. The synthesis method according to claim 1, characterized in that, The palladium catalyst is selected from one or more of the following: bis(dibenzylacetone)palladium, tri(dibenzylacetone)dipalladium, palladium acetate, di-tert-butylpalladium, allyl palladium chloride dimer, palladium trifluoroacetate, di-M-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium, and cyclopentadienylallylpalladium.

5. The synthesis method according to claim 1, characterized in that, The chiral phosphine ligand is selected from one of formulas L1 to L12; wherein, formulas L1 to L12 are: 。 6. The synthesis method according to claim 1, characterized in that, The organic solvent is selected from one or more of toluene, trifluorotoluene, o-difluorobenzene, hexafluorobenzene, acetone, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, carbon tetrachloride, dichloromethane, chloroform, and dichloroethane.

7. The synthesis method according to claim 6, characterized in that, The organic solvent is a drying solvent.

8. The synthesis method according to claim 1, characterized in that, The reaction temperature is from -20 ℃ to 80 ℃, and the reaction time is from 12 h to 48 h.

9. The synthesis method according to claim 1, characterized in that, The order of feeding the reaction is as follows: First, the palladium catalyst and the chiral phosphine ligand are dissolved in the organic solvent, then compound 2 is added, the temperature is adjusted to the reaction temperature, and finally compound 1 is added. Alternatively, the palladium catalyst and the chiral phosphine ligand are first dissolved in the organic solvent, then compound 2 and the organic solvent are added, the temperature is adjusted to the reaction temperature, and finally compound 1 is added.

10. A chiral silanetetrahydro-1-naphthylamine compound synthesized by the method according to any one of claims 1-9.

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